Intermediates of cephalosporin derivatives and their production methods
A manufacturing method and technology of crystals, which are applied in the direction of medical preparations containing active ingredients, antibacterial drugs, pharmaceutical formulas, etc., can solve the problems of unrecorded preparation methods, not crystals, and no records of crystals, etc., and achieve a good yield Effect
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Embodiment 1
[0261]
[0262] [chemical formula 25]
[0263]
[0264] Step 1: Synthesis of Compound 10
[0265] Under a nitrogen atmosphere, compound 9 (25.0 kg, 164.3 mol) was dissolved in methanol (125 L), and cooled to -7°C. A sodium hypochlorite aqueous solution (11 to 12%) (135 L, 261.1 mol) was added dropwise over 2 hours and 30 minutes at -7°C, followed by stirring at -7°C for 3 hours. The reaction solution was added to a mixed solution of sulfuric acid water and methanol at 40° C., stirred for 1 hour and 30 minutes, and the precipitated solid was collected by filtration to obtain a non-dried solid. The undried solid was recrystallized from methanol-water and dried to obtain compound 10 (46.0 kg, content 57.3%, yield 86.1%).
[0266] Step 2: Synthesis of Compound 11
[0267] Compound 10 (content conversion: 26.0 kg, 139.3 mol) was dissolved in DMA (130 L) in a nitrogen atmosphere, pyridine (30.9 kg, 391.2 mol) was added, and the mixture was heated to 50°C. An anisole (78 L) ...
Embodiment 2
[0277] 1st process
[0278] [chemical formula 26]
[0279]
[0280] Process 1
[0281] Under nitrogen atmosphere, Compound 2 (254.3 g, 592 mmol) was dissolved in DMA (600 mL), and cooled to -5°C. Methanesulfonyl chloride (67.83 g, 592 mmol) was added, triethylamine (59.92 g, 592 mol) was added dropwise at -5°C over 25 minutes, and stirred at -5°C for 60 minutes. This was added to a suspension of compound 1 (200.0 g, 493 mmol) in ethyl acetate (1 L), and N-methylmorpholine (99.83 g, 987 mmol) was added dropwise at -5°C for 20 minutes, and Stirring was carried out for 60 minutes.
[0282] The reaction solution was added to a mixed solution of ethyl acetate and dilute hydrochloric acid to perform extraction. The organic layer was washed with water, an aqueous sodium bicarbonate solution, and water, and then concentrated under reduced pressure. After adding n-heptane to the obtained residue to precipitate a solid, the compound 6 (373.1 g, yield 97.0%) was obtained by colle...
Embodiment 3
[0285] 2nd process
[0286]
[0287] [chemical formula 27]
[0288]
[0289] Step 1: Synthesis of the ansolvate seed crystal A of compound 3
[0290] Under a nitrogen atmosphere, Compound 6 (120.00 g, 154 mmol) was dissolved in dichloromethane (600 mL), and cooled to -20°C. 39% peroxyacetic acid (29.99 g, 154 mmol) was dripped over 50 minutes, and it stirred at -20 degreeC for 30 minutes. The reaction liquid was added to an aqueous sodium bisulfite solution for extraction. The organic layer was washed with water, and concentrated under reduced pressure. After adding ethanol to the obtained residue to precipitate crystals, the crystals were cooled to 0° C., collected by filtration, and air-dried to obtain ansolvate-free seed crystal A of Compound 3 (92.10 g, yield 75.2%).
[0291] 1 H-NMR (CDCl 3 )δ: 1.41(s,9H)1.52(s,9H)1.58(d,J=6.06Hz,6H)3.42(d,J=18.69Hz,1H)3.78-3.86(m,4H)4.23(d,J =12.63Hz, 1H) 4.58 (d, J = 3.79Hz, 1H) 5.01 (d, J = 12.38Hz, 1H) 5.21-5.32 (m, 2H) 6....
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