New Patent, Tedizolid phosphate, Suzhou MiracPharma Technology Co Ltd, Zheren Pharmaceutical Nanjing Co Ltd, WO 2016058467

Tedizolid phosphate

Suzhou MiracPharma Technology Co Ltd; Zheren Pharmaceutical Nanjing Co Ltd

WO-2016058467   click for patent

SUZHOU MIRACPHARMA TECHNOLOGY CO., LTD [CN/CN]; Room 1305, Building 1 Lianfeng Commercial Plaza, Industrial District Suzhou, Jiangsu 215000 (CN).
ZHEREN PHARMACEUTICAL NANJING CO., LTD [CN/CN]; Qiaolin Industry Park 32-71, Pukou District Nanjing, Jiangsu 211806 (CN)

Disclosed is a method for preparing tedizolid phosphate (I), and the preparation step thereof comprises producing the tedizolid phosphate (I) by means of a coupling reaction of a compound of formula II and a compound of formula III. The preparation method uses easily available raw materials and a simple process, is economical and environmentally friendly, and is suitable for industrial production.

Process for preparing tedizolid phosphate (TD-P), useful for treating bacterial infection. The present filing represents the first PCT and first filing to be seen from Suzhou Miracpharma and Zheren Pharmaceutical, respectively, that focuses on tedizolid; however this case was first seen as a Chinese national filing (assigned to Suzhou Miracpharma), published in February 2015. The drug was developed and launched by Dong-A ST and licensees Cubist Pharmaceuticals and Bayer, for treating acute bacterial skin and skin structure infections.

Tedizolid phosphate by Charpy Manchester (Cubist) pharmaceutical companies to develop a oxazolidinone antibiotics. Tedizolid phosphate in June 2014 to obtain FDA approval in the United States, the trade name Sivextro. The drug was first approved by the FDA in the second generation oxazolidinone antibiotics, and linezolid compared to the previous generation, Sivextro some bacteria in vitro inhibitory activity 2-8 times higher security to a certain extent also improved. Because compound Tedizolid not have standard Chinese translation, so the applicant where it is transliterated as "Thai to acetazolamide."

Thailand phosphate to acetazolamide (Tedizolid phosphate) Chemical name: {(5R) -3- [3- fluoro-4- [6- (2-methyl--2H- tetrazol -5-yl) pyridine-3 yl] phenyl] -2-oxazolone -5-yl} methanol phosphate (I), having the formula:

Preparation of phosphate Thailand to acetazolamide has been reported, PCT Patent No. WO2005058886, No. WO2010042887 and "European Journal of Medicinal Chemistry" 2011 on 1027 - 1039 Section 46 were reported to temozolomide and phosphate Thai analog synthesis and related intermediates. Comparative summary of these methods, which are synthetic route from Intermediate A and Intermediate B (or intermediate B ') by an aryl coupling reaction to achieve.

Wherein 2- (2-methyl-tetrazol-5-yl) -5-bromopyridine (Intermediate A) is generated by a tetrazolium derivative azide reaction of 2-cyano-5-bromopyridine, and then the use of methyl iodide or dimethyl sulfate, etc. methylating reagent for tetrazole ring methylation reaction, to give 2- (2-methyl-tetrazol-5-yl) -5-bromopyridine (intermediate A ) and (1-methyl-tetrazol-5-yl) -5-bromo pyridine (by-product) in a mixture of 2, by column chromatography or recrystallization to give the intermediate separator A.

Intermediate B or B 'by R-3- (3- fluoro-4-iodo-phenyl) -2-oxo-5-oxazolidinyl methanol formed organoboron reagent or an organotin reagent, the reagent is Stille or Suzuki coupling reactions, realize intermediate a coupling.

This shows that the existing preparation method has the steps for preparing long, difficult to obtain raw materials and high costs weaknesses; preparation and use of organotins on equipment and environmental requirements are high, there is environmental pollution risks. In addition, intermediate B or B 'structure halogens fluorine and iodine exist, reducing the selective formation of organometallic reagents, so that an increase in side effects, product quality is difficult to be effectively controlled.

Example One:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid (II) (2.15g, 10.5mmol) , R-3- (3- fluoro - 4-iodo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (4.17g, 10mmol) , tetrakis (triphenylphosphine) palladium (0.23g, 0.2mmol), 1M phosphoric acid 15mL of toluene solution of potassium 30mL, warmed to reflux, maintained the reaction at reflux for 10-12 hours, TLC the reaction was complete. Ethyl acetate was added 30mL, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized, and dried in vacuo to give a white The solid phosphoric acid to Thailand acetazolamide (I) 3.82g, yield% 84.9, ¹ the H NMR (of DMSO-d6): D 8.92 (S, IH), 8.20 (m, 2H), 7.74 (T, IH), 7.66 ( dd, 1H), 7.50 (dd , 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (m, 1H), FAB-MS m / Z: 451 [the m the H +] ⁺ .

 

Example Two:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester (II) (3.01g, 10.5mmol), R-3- (3 - fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (3.69g, 10mmol), [1,1'- bis (diphenylphosphino) ferrocene Fe] dichloropalladium / dichloromethane complex (0.15g, 0.2mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 50mL, heated to 110 ℃, the reaction was stirred for 4-5 hours , TLC the reaction was complete. Ethyl acetate was added 50mL, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized, and dried in vacuo to give a white Thai solid phosphoric acid to acetazolamide (I) 4.02g, yield 89.3%.

Example Three:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) -5-bromo - pyridine (IV) (2.4g, 10mmol), alcohol-based dual which diborane ( 1.27g, 5mmol), 1,1'- bis (diphenylphosphino) ferrocene palladium dichloride (0.82g, 1mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 30mL , heated to 110 deg.] C, the reaction was stirred for 4 hours. Cooled to room temperature, still under nitrogen, was added to the system for R-3- (3- fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (3.69 g, 10mmol), 1,4- dioxane and 20mL 5M potassium phosphate 0.5mL, again heated to 100 ℃, the reaction was stirred for 4 hours, TLC the reaction was complete. Ethyl acetate was added 50mL, filtered and the filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized vacuo Thai dried to give a white solid phosphoric acid to acetazolamide (I) 3.34g, yield 74.2%.

IV (Preparation of the intermediate II) Example:

In a three-necked reaction flask 2- (2-methyl-tetrazol-5-yl) -5-bromo - pyridine (IV) (2.4g, 10mmol) was dissolved in 25mL anhydrous tetrahydrofuran, cooled to -55 deg.] C, was added dropwise isopropylmagnesium chloride (1M, 15ml), dropwise after completion of the reaction was stirred for 30 minutes. To the reaction system was added trimethylborate (1.25g, 12mmol), stirring was continued for 4-5 hours the reaction. At low temperature with saturated ammonium chloride solution to quench the reaction, and the reaction solution was poured into dilute hydrochloric acid and 30mL 1N reaction at room temperature for 1 hour. Extracted three times with ethyl acetate, the combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the resulting solid is washed with petroleum ether, and then recrystallized from water to give a white solid of 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid (II) 1.6g, 78.0% yield, m the MS-FAB / Z: 206 [the m the H +] ⁺ .

Embodiment 5 (preparation of intermediate II):

In a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) -5-bromo - pyridine (IV) (2.4g, 10mmol) , alcohol-based dual which diborane (1.27g, 5mmol ), 1,1'-bis (diphenylphosphino) ferrocene palladium dichloride (0.82g, 1mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 50mL, heated to 110 ℃, the reaction was stirred for 8-10 hours to complete the reaction by TLC. Extracted three times with ethyl acetate, the combined organic phases were washed with brine, dried over anhydrous sodium sulfate. Concentrated, ethyl acetate and n-hexane (1:4) recrystallized to give an off-white solid 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester (II) 2.48g, yield 86.4 %, the MS-FAB m / Z: 288 [the m the H +] ⁺ .

Six (preparation of intermediate III) Example:

Under nitrogen, in a three-necked reaction flask R- glycidyl tosylate (TG) (2.28g, 10mmol) and N, N- dimethylformamide 25mL, stirred and dissolved, was added cesium carbonate (0.33 g, 1mmol) and 3-fluoro-4-bromo - phenyl isocyanate (V) (2.15g, 10mmol) , was heated to 100 ℃, after 1 hour, TLC detection completion of the reaction. Recovery of the solvent under reduced pressure, the residue was dissolved with dichloromethane and water, the organic phase was separated, the aqueous phase was extracted twice with methylene chloride, concentrated under reduced pressure to give an oil which was R-3- (3- fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol p-toluenesulfonate (the VI), without further purification, 1N hydrochloric acid was added directly to the reaction at 50 ℃ 5 hours and extracted three times with dichloromethane The combined organic phase was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 30mL of triethyl phosphate was added at room temperature, phosphorus oxychloride (2.2mL, 24mmol), stirred for 2-3 hours. 30mL of ethyl acetate was added, stirred for half an hour, poured into 50g of ice-water, and stirring was continued for 2 hours at 0 deg.] C, and a solid white precipitate was filtered, the filter cake washed with acetone and dried to give an off-white solid R-3- (3-fluoro-4-bromo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) 2.45g, yield 66.4%, FAB-MS m / z: 369 [m + H ] ⁺ .

Six (preparation of intermediate III) Example:

 

Under nitrogen, in a three-necked reaction flask R- glycidyl tosylate (TG) (2.28g, 10mmol) and tetrahydrofuran 50mL, stirred and dissolved, was added lithium iodide (0.14g, 1mmol) and 3- fluoro-4 - phenyl isocyanate (V) (2.63g, 10mmol) , was heated to reflux. after 2 hours, TLC detection completion of the reaction. Recovery of the solvent under reduced pressure, the residue was dissolved with dichloromethane and water, the organic phase was separated, the aqueous phase was extracted twice with methylene chloride, concentrated under reduced pressure to give an oil which was R-3- (3- fluoro-4 - phenyl) -2-oxo-5-oxazolidinyl methanol p-toluenesulfonate (the VI), without further purification, 1N hydrochloric acid was added directly to the reaction at 50 ℃ 5 hours and extracted three times with dichloromethane The combined organic phase was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 30mL of triethyl phosphate was added at room temperature, phosphorus oxychloride (2.2mL, 24mmol), stirred for 2-3 hours. 30mL of ethyl acetate was added, stirred for half an hour, poured into 50g of ice-water, and stirring was continued for 2 hours at 0 deg.] C, and a solid white precipitate was filtered, the filter cake washed with acetone and dried to give an off-white solid R-3- (3-fluoro-4-iodo - phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) 2.65g, yield 63.7%, FAB-MS m / z: 417 [m + H ] ⁺ .

 

//////New Patent, Tedizolid phosphate, Suzhou MiracPharma Technology Co Ltd,  Zheren Pharmaceutical Nanjing Co Ltd, WO 2016058467