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Method for preparing oxazolidinone compound and intermediate thereof

One compound and one technology, applied in the field of pharmaceutical chemical synthesis, can solve problems such as unsuitable for industrial production, many side reactions, and low purity

Inactive Publication Date: 2015-04-08
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the purity and yield of intermediate 3 prepared by the first step reaction were low (HPLC: 89.8%, yield: 66%); the last step of coupling reaction, using a strong base (lithium hexamethyldisilicide) resulted in side effects There are many reactions, more impurities are introduced, post-processing is difficult, and the operation is cumbersome; the last step takes a long time to react, and the purity of the prepared tedizolid is low, which needs to be purified many times, the operation is cumbersome, and the Pd residue after purification is still high; the reaction Need to use anhydrous solvent, not suitable for industrial production
[0015] At present, there are relatively few reports about the preparation method of tedizolid in the literature. In the existing method, the operation is complicated, the reaction time is long, the production cost is high, and the total yield is low. Low purity, not suitable for industrial production

Method used

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  • Method for preparing oxazolidinone compound and intermediate thereof
  • Method for preparing oxazolidinone compound and intermediate thereof
  • Method for preparing oxazolidinone compound and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Embodiment 1: the preparation of the compound shown in formula IIa

[0080]

[0081] (1), the preparation of 2-cyano-5-bromopyridine:

[0082] Dissolve 100 grams of 2,5-dibromopyridine in 1 liter of dimethylformamide, add 32 grams of copper cyanide and 17.8 grams of sodium cyanide to the solution at room temperature, and stir the solution at 150 °C for 7 hours to react. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried, filtered and concentrated in vacuo to afford 54 g of the title compound, 70% yield. 1 H-NMR (CDCl 3 ) 8.76 (s, 1H), 7.98 (dd, 1H), 7.58 (dd, 1H).

[0083] (2), the preparation of 2-(tetrazol-5-yl)-5-bromopyridine:

[0084] Dissolve 10 grams of 2-cyano-5-bromopyridine in 100 milliliters of dimethylformamide, add 5.33 grams of sodium azide and 4.4 grams of ammonium chloride to the solution at room temperature, and the solution is a...

Embodiment 2

[0089] Example 2: Preparation of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinylmethanol (i.e., compound i'):

[0090]

[0091] (1), the preparation of N-benzyloxyformyl-3-fluoroaniline (1-7):

[0092] 100 g of 3-fluoroaniline was dissolved in 1 liter of tetrahydrofuran (THF), and 150 g (1.8 mol) of bicarbonate

[0093] Sodium (NaHCO 3 ) into the solution, and after cooling to 0°C, 154 ml of N-benzooxycarbonyl chloride (CbzCl) was slowly added into the solution for reaction. The reaction mixture was continuously reacted at 0°C for 2 hours with stirring, and then the reaction system was extracted with 0.5 liter of ethyl acetate. After separation, the organic layer was washed with brine, washed with anhydrous magnesium sulfate (MgSO 4 ) was dried and concentrated in vacuo, and the residue was washed twice with n-hexane to obtain 132 g of the title compound as white crystals in a yield of 85%.

[0094] (2) Preparation of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinylmethano...

Embodiment 3

[0099] Example 3: Preparation of tedizolid (compound shown in TD):

[0100]

[0101] In a 500ml three-neck flask equipped with a reflux condenser and a thermometer, add 1.57g of Pd(OAc) 2 , 3.7g PPh 3 Dissolve in 150 ml DMF, replace with nitrogen, then add 33.75 ml triethylamine, stir at 70°C until the solution turns red and black, add 47.2 g of (R)-3-(4-iodo-3 prepared in Example 2 -fluorophenyl)-2-oxo-5-oxazolidinylmethanol (compound i') and 34.4g of the compound shown in formula IIa prepared in Example 1, dissolved in 100ml DMF solution, under nitrogen protection, at 90°C Stir the reaction for 2h, monitor the reaction by TLC, and filter it through celite while it is hot. Concentrate to 50ml at 70°C, add 500ml of purified water, stir for 1.0h, filter, wash the filter cake with 50ml of 50% aqueous methanol (volume concentration), and dry at 50°C for 8h. Add 430ml of 50% methanol aqueous solution (volume concentration) to the obtained solid, heat to 70°C for beating for ...

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PUM

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Abstract

The invention relates to a method for preparing an oxazolidinone compound and an intermediate thereof. Specifically, two fragments are coupled to prepare the oxazolidinone compound by virtue of Suzuki reaction. The method is simple in process, short in reaction time and high in yield and is suitable for industrial production. Furthermore, the method for preparing the intermediate of the oxazolidinone compound has the advantages of simplicity in operation, high yield and low cost.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of oxazolidinone compounds and intermediates thereof. Background technique [0002] Oxazolidinones as a class of chemical constituents find wide application in drugs for the treatment and prevention of medical diseases such as bacterial infections and atherosclerosis. Various structures of oxazolidinone derivatives are known. For example, US4461773, US4476136, US4250318 and the like disclose mono-substituted or di-substituted derivatives of 3-phenyl-2-oxazolidinone. [0003] Tedizolid (Tedizolid) is a new type of oxazolidinone antibiotics, its phosphate (tedizolid phosphate) has been approved by the FDA for the treatment of Staphylococcus aureus (including methicillin-resistant strains, methicillin-sensitive strains) and acute bacterial skin and skin structure infections (ABSSSI) caused by Gram-positive bacteria such as various Streptococcus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07F9/6558C07F5/02C07C213/04C07C219/06
CPCC07C219/06C07D413/14C07F5/02Y02P20/55C07C213/04C07F5/025C07F9/65583
Inventor 袁建栋陈耀杭文明
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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