Preparation of Tedizolid Phosphate Disodium Salt_Industrial Additive

Overview^[1-2]

Tedizolid Phosphate is a second-generation oxazolidinone antibiotic developed by Dong-A Pharmaceutical. Sivextro is approved for the treatment of acute bacterial skin and skin soft tissue infections (ABSSSI) and is intended to treat Serious or life-threatening infection. Tedizolid phosphate is rapidly hydrolyzed by phosphatase in the body into the active prodrug tedizolid, which exerts its medicinal effect by inhibiting bacterial protein synthesis. Has a longer half-life compared to linezolid.

Tedizolid phosphate disodium salt is an important intermediate for the preparation of tedizolid phosphate. Due to its strong hygroscopicity and instability, tedizolid phosphate disodium salt is not suitable for use in solid preparations, such as the preparation of tablets, but its It has good solubility and is therefore suitable for the preparation of intravenous preparations. The disodium salt solution is freeze-dried to prepare sterile lyophilized powder for injection. The disodium salt is very easy to dissolve and is conducive to redissolution in sterile water to obtain a solution. The pp adhesion promoter is directly added to the intravenous infusion bag. Can contain isotonic solutions such as 0.9% sodium chloride solution or 5% glucose solution.

Crystal form^[2]

Preparation of Tedizolid Phosphate Disodium Salt Crystal Form I:

Put 100 mg of tedizolid phosphate disodium salt into a 50 ml reaction bottle, add 1 ml of water, stir and dissolve, add 3 ml of methanol dropwise, precipitate, filter with suction, and use a mixed solvent of water and methanol (volume ratio 1:1) Wash and vacuum dry at 40°C for 6 hours to obtain 69 mg of needle-like crystals, which is crystal form I, with a yield of 69.0%;

After measurement, its X-RPD pattern is shown in Figure 1, and its DSC-TGA pattern is shown in Figure 2. Thermoplastic elastomer.

1H-NMR (600MHz, DMSO, δppm): 3.59(d,1H),3.72(d,1H),3.92(t,1H),4.15(t,1H), 4.49(s,3H),5.28 (s,1H),7.52(d,1H),7.65(m,2H),8.25(dd,2H),8.93(s,1H).

Preparation of Tedizolid Phosphate Disodium Salt Crystal Form II:

Put 100 mg of tedizolid phosphate disodium salt into a 50 ml reaction bottle, add 1 ml of water, stir and dissolve, add 3 ml of methanol dropwise, precipitate, filter with suction, and use a mixed solvent of water and methanol (volume ratio 1:1) Wash and dry at room temperature to obtain 71 mg of needle-like crystalline solid, which is crystal form II, with a yield of 71.0%;

After measurement, its X-ray powder diffraction pattern is shown in Figure 3, and its DSC-TGA pattern is shown in Figure 4.

Preparation^[1]

(1) Add 1g tedizolid phosphate and 15ml isopropyl alcohol to a 50ml single-mouth bottle and stir at room temperature. Add 15ml of an ether solution containing 1.55g Ph3CNa dropwise from a constant pressure dropping funnel. Complete the addition in 40 minutes and control the reaction temperature. At 40-45°C, the solution gradually changes from light red to white during the reaction. TLC monitors the reaction. Stop the reaction after 2 hours, and the reaction solution will be used for later use;

(2) Add 0.1g of activated carbon to the reaction solution obtained in step (1) for decolorization for 0.5h, filter with suction, extract the filtrate twice with 10ml of methylene chloride, combine the aqueous phases, and use the obtained aqueous phase for later use;

(3) Add 60 ml of diethyl ether dropwise to the aqueous phase obtained in step (2). After the dropwise addition is completed for 1 hour, stir and crystallize at room temperature for 0.5 h, filter with suction, rinse twice with 10 ml of diethyl ether, and dry under vacuum to obtain Tedizole Phosphate. Amine disodium salt 0.96g, yield 87.45%. The moisture gain is 1.2%, and the purity is 99.91%.