Preparation method of tedizolid phosphate_industrial additives

Background and overview^[1]

Tedizolid phosphate, also known as tedizolid phosphate, tedizolid phosphate, tedizolid phosphate, chemical name is [(5R)-3-{3-fluoro-4-[ 6-(2-Methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-2-oxoxazolidin-5-yl]methyl hydrogen phosphate, the molecular formula is C17H16FN6O6P. Tedizolid phosphate is a second-generation oxazolidinone antibiotic developed by Dong-APharmaceutical. Its phase III clinical trial showed that its clinical effect is equivalent to linezolid in terms of gastrointestinal tract and thrombocytopenia. It has fewer adverse reactions than linezolid and the incidence of drug resistance is also lower. Some trials have shown that tedizolid is also better tolerated than vancomycin. FDA-approved dosage forms include injections and tablets, which are convenient for clinical switching. The dosage is once a day for six days, and plinezolid is used twice a day for ten days, which is more convenient for clinical use. Therefore, in view of its good clinical effect, smaller dose and shorter administration period, it is suitable for a wide range of people and has a broad market capacity.

Preparation method^[5]

A preparation method of high-purity tedizolid phosphate, including the following steps:

Step 1:

Add 4.3kg 2-methyl-5-(5-bromopyridin-2-yl)tetrazole, 5.4kg pinacol diborate, 3.5kg potassium acetate, 35.0kg 1,4-di Oxygen hexacyclic ring, start stirring, replace with nitrogen twice, add 0.29kg of tetrakis (triphenylphosphine) palladium under nitrogen protection, heat to 70°C, react for 4 hours, stop heating after the reaction is completed, add 22.0kg of n-heptane alkane, cool to 5°C, keep stirring for 1 hour, remove the nitrogen protection, discharge and filter, rinse the filter cake once with 4.0kg n-heptane, filter until no filtrate drips, collect the filter cake and put it into a vacuum drying oven at 50°C Dry at high temperature, and collect and weigh the material after 8 hours to obtain pinacol borate;

Step 2:

Step 1: Add 3.8kg pinacol borate and 4.7kg (5R)-3-(4-bromo-3-fluorophenyl)-5-hydroxymethyloxazolidine-2- into the reactor Ketone, 24.3kg 1,4-dioxane and 13.8kg potassium carbonate solution, start stirring, replace with nitrogen twice, add 0.67kg tetrakis (triphenylphosphine) palladium under nitrogen protection, heat to 60°C, react for 5 hours , after the reaction is completed, remove the nitrogen, cool to 25°C, add 9.3kg of purified water, then cool to 10°C, keep stirring for 0.5h, filter, and rinse the filter cake once with 4.7kg of 1,4-dioxane, and shake Filter until no liquid flows out and collect the filter cake;

Step 2: Add the filter cake obtained in step 1 and 55.0kg N,N-dimethylacetamide to the reactor, start stirring, heat to 60°C, keep stirring for 1 hour, cool to 20°C, filter, filter cake Rinse with 4.3kgN,N-dimethylacetamide and collect the filtrate;

Step 3: Add the filtrate obtained in step 2, 1.4kg L-cysteine ​​and 1.4kg triethylamine into the reactor, start stirring, avoid light reaction, replace with nitrogen once, heat to 60°C, react for 16 hours, Cool to 20°C, react for 0.5h, filter with suction, rinse the filter cake once with 13.0kg N,N-dimethylacetamide, and collect the filtrate;

Step 4: Add the filtrate obtained in step 3 to the reactor, start stirring, cool to 10°C, add purified water, control the temperature at 15°C during the adding of purified water, after the purified water is added, at 20°C temperature, stir for 1 hour, filter, and rinse the filter cake once with 4.7kg N,N-dimethylacetamide/purified water mixed solution and 3.7kg anhydrous methanol respectively, filter until no liquid flows out, and collect the filter cake. ;

Step 5: Add the filter cake obtained in step 4 and 55.0kg anhydrous methanol into the reactor, start stirring, control the temperature to 25°C, keep stirring for 1 hour, filter, and rinse the filter cake once with 18.0kg anhydrous methanol. , filter until no liquid flows out, collect the filter cake, place the filter cake in a vacuum dryer, dry it for 5 hours at a temperature of 60°C and a vacuum degree of greater than or equal to 0.09MPa, collect and weigh, and obtain (R) -3-[4-[2-(2-methyltetrazol-5-yl)pyridin-5-yl]-3-fluorophenyl]-5-hydroxymethyloxazolidine;

Step 3: Under nitrogen protection, add 1.0kg (R)-3-[4-[2-(2-methyltetrazol-5-yl)pyridin-5-yl]-3 into the reactor -Fluorophenyl] water-based amino resin-5-hydroxymethyloxazolidine, 0.32kg triethylamine and 17.8kg tetrahydrofuran, start stirring, cool to 0°C, slowly add 2.14kg phosphorus oxychloride/tetrahydrofuran solution, the addition is completed , control the temperature to 0°C, stir the reaction for 5 hours, take out the mixed liquid, add 20.0kg of purified water to the reactor, cool to 5°C, start stirring, add the above mixed liquid, control the feeding process, control the system temperature to 5°C, and complete the feeding. Raise the temperature to 25°C, stir for 1 hour, filter, rinse the filter cake once with 1.0kg purified water, filter until no liquid flows out, collect the filter cake; put the filter cake into the reactor, add 5.9kg methanol and 0.7kg Purified water, keep stirring for 0.5h, filter, rinse the filter cake with 0.7kg methanol once, filter until no liquid flows out, collect the filter cake, place the filter cake in a hot air circulation drying oven, heat it to 40°C, and dry After 4 hours, tedizolid phosphate was obtained, with a calculated yield of 75.68% and a purity of 99.95%.

Refining method^[1][4]

Report 1,

Dissolve 45g tedizolid phosphate in purified water (185ml), add 8% sodium hydroxide solution dropwise at a controlled internal temperature of 15 to 25°C, adjust the pH to 7.5, add activated carbon (2.25g), and control the internal temperature. The temperature is 15~25°C, stir for 2 hours, filter, transfer the filtrate to the reaction bottle, slowly add acetone (1.73L), stir for 2 hours, a large amount of solid will precipitate, filter, wash the filter cake with a small amount of acetone, and drain to obtain phosphoric acid special salt.Zozolamide sodium salt.

Transfer the tedizolid phosphate sodium salt obtained above to the reaction bottle, add purified water (185 ml) to dissolve. Control the internal temperature to 15-25°C and add 3% hydrochloric acid solution (365ml) dropwise. After the dropwise addition is completed, stir for 1 hour at the same temperature and slowly add acetonitrile (890ml). Stir and crystallize at 15-25°C for 3 hours at a stirring speed of 200 r.p.m. Filter, wash with a small amount of purified water and acetone, drain, and dry under reduced pressure at 65-70°C to obtain 40.2g of tedizolid phosphate, with a yield of 89.3%. .

Report 2,

A method for refining tedizolid phosphate:

(1) Add 50g of crude tedizolid phosphate to 200ml of water, then add 4g of tributylphosphine, keep it at 15-25°C, slowly add 1mol/L sodium hydroxide solution dropwise while stirring, and adjust to pH = 8. Add 4g of activated carbon, stir and decolorize for 1.5 hours, and then filter to obtain tedizolid phosphate sodium salt solution;

(2) Slowly add the obtained tedizolid phosphate sodium salt aqueous solution dropwise into 1000 ml tetrahydrofuran, stir for 12 hours while maintaining 15-25°C, filter, and wash the filter cake with tetrahydrofuran to obtain tedizolid phosphate sodium salt Wet product 78g;

(3) Add 390ml of purified water to the obtained tedizolid phosphate sodium salt wet product, stir, add glacial acetic acid dropwise to adjust to pH=6.5, then add 15.6g of activated carbon, stir for 6 hours to decolorize, and filter;

(4) Add 390ml tetrahydrofuran to the filtrate, then add 210ml anhydrous citric acid in batches, adjust the pH=2~3; then, while maintaining 15-25℃, stir for 48h to crystallize, filter, filter The cake was washed with purified water, and the filter cake was dried to obtain 43.2g of tedizolid phosphate, with a yield of 86.4%.

The purity determined by HPLC is: 99.94%, with a maximum single impurity of 0.02%.

Preparations^[2-3]

Report 1, Tablets

Name of raw materials and excipients Percentage of raw materials and excipients (%) Amount of raw materials and excipients for 1000 tablets (g)

Tedizolid phosphate 50.00 50.00

Spray dried lactose 36.50 36.50

Starch 10.00 10.00

Crosscarmellose sodium 2.00 2.00

Silicon dioxide 1.00 1.00

Magnesium stearate 0.50 0.50

Total 100.00 100.00

Preparation method:

1) Combine the raw material tedizolid phosphate and excipients in each of the above prescriptions, namely spray-dried lactose, microcrystalline cellulose PH102 (starch), croscarmellose sodium (low-substituted hydroxypropylcellulose), Pass silicon dioxide and magnesium stearate through an 80-mesh sieve respectively and set aside.

2) Weigh the raw materials tedizolid phosphate, spray-dried lactose, microcrystalline cellulose PH102 (starch), and croscarmellose sodium (low-substituted Albemarle hydroxypropylcellulose) according to the above prescription amounts. , silica, and magnesium stearate are placed together in a three-dimensional mixer and mixed evenly.

3) Take the mixed materials, punch them into flat tablets using a rotary tablet press φ10, and package them.

Report 2, liposomes

Weigh soy lecithin and cholesterol at a mass ratio of 6:1, add 2 mL of absolute ethanol and rotary evaporate at 55°C (vacuum degree 0.05MPa) to form a dry film, add 5 mL of calcium acetate aqueous solution (120 mmol/L), and hydrate Disperse evenly for 5 minutes (ultrasonic dispersion if necessary) to prepare blank liposomes. Place the prepared blank liposomes in a dialysis bag (8000-10 Da) and dialyze with physiological saline three times, each time lasting 1 hour. After dialysis, the blank liposomes are added with tedizolid phosphate solution (to increase water solubility, react with NaOH to form disodium salt), and are obtained after incubation in a 50°C water bath for 15 minutes.