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With hydrogenchloride; In diethyl ether; di-isopropyl ether; at -20 - -10℃; for 3.0h;Inert atmosphere;
under nitrogen protection,10 g of cefazolin was added to a 500 ml reaction flask,With stirring at -20 C, Add isopropyl ether 100mlEther 100ml,0.082 mol of HCl gas and -10 C for 3 hours.Filter, filter cake with ether, 30 C vacuum drying 12 ~ 16h,To obtain cefazolin hydrochloride 9.2g,Yield 86%HPLC detection purity of 99.4%The isopropyl ether solvent remained 0.14%, the ether solvent remained 0.1%, the acetone solvent remained 0.04%, the methanol was 0.07%, the ethanol was 0.07%, and the moisture content was 2.0%.
Cefozopran free base (100 g) was suspended in water (400 ml). The suspended slurry was cooled to 1O0C to 150C and 12 N hydrochloric acid (200 ml) was added over the period of 20 minutes to 25 minutes to obtain a clear solution. Enoantichromos carbon (10 g) was added to the solution and stirred for 30 minutes at 1O0C to 150C. The solution was filtered through a Celite bed and washed with water (200 ml). The resultant solution was filtered through 0.45 μ filter. 20% w/v aqueous sodium hydroxide solution (300 ml) was added to the filtered solution over the period of 30 minutes to 45 minutes at 2O0C to 250C. The resultant slurry was stirred for 2 hours at 2O0C to 250C and 1 hour at 100C to 150C. The solid was filtered and washed with water (200 ml) followed by tetrahydrofuran (2 X 200 ml; one slurry washing followed by running washing). The solid was dried at 500C to 55C for 16 hours to obtain title compound.Yield: 80 g HPLC purity: 99%Residual solvent content (μg/g): methanol - 17; ethanol - 47; acetone - not detected; isopropanol - not detected; tetrahydrofuran - 23;
(6R,7R)-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino}-3-(imidazo[1,2-b]pyridazin-1-ium-1-ylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate hemihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cefozopran hydrochloride (100 gm) was added to N, N-dimethylformamide (300 ml) at 2O0C to 250C portion- wise in 5 minutes to 10 minutes. Water (50 ml) was added to the mixture with fast stirring at 2O0C to 250C to obtain a clear solution. The pH of the solution was adjusted to 1.0 to 2.2 with 35% aqueous hydrochloric acid solution at 2O0C to 250C followed by the addition of activated carbon (5 g) and stirring for 5 minutes to 10 minutes. The mixture was filtered and washed with N, N-dimethylformamide (100 ml) at 2O0C to 250C. The pH was readjusted to 3.5 to 4.5 with tributylamine (10 to 20 ml), stirred for 60 minutes to 90 minutes at 2O0C to 250C, filtered and washed with N, N- dimethylformamide (100 ml) and isopropanol (200 ml). The solid obtained was stirred in isopropanol (500 ml) for 2 hours, filtered, washed with isopropanol (100 ml) and dried at 4O0C to 450C to obtain the title compound.Chloride Content: 3.4% w/wN, N-dimethylformamide Content (by NMR): 11.8% w/wYield: 70.O g
7β-amino-3-[(imidazo[1,2-b]pyridazinium-1-yl)methyl]-3-cephem-4-carboxylate hydrochloride[ No CAS ]
[ 113981-44-5 ]
Yield
Reaction Conditions
Operation in experiment
7β-amino-3-[(imidazo[l,2-b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate hydrochloride (100 g) and 5r-l,3-benzothiazol-2-yl (2Z)-(5-amino-l,2,4-thiadiazol-3- yl)(methoxyimino)ethanethioate (240 g) were added to a mixture of tetrahydrofuran (1.0 L) and water (350 ml) at 150C to 2O0C. A mixture of tributylamine in tetrahydrofuran (70 g/70 ml) was added to the reaction mixture in 20 minutes duration at 150C to 250C to attain a pH of 6.8 to 7.2 and stirred for 5 hours at 250C to 3O0C. The reaction mixture was cooled to 1O0C to 150C and a mixture of dichloromethane (1.5 L) and de-mineralized water (200 ml) was added at 1O0C to 150C. The reaction mixture was stirred for 15 minutes and the layers were separated. Vacuum was applied to the water layer to remove excess tetrahydrofuran at 150C to 2O0C. 6 N hydrochloric acid (40 ml) was added to the reaction mixture at 1O0C to 150C over a 5 minute to 10 minute duration to attain a pH of about 1.4. Enoantichromos carbon (10 g) and Celite (10 g) were added to the reaction mixture and stirred for 20 minutes at 1O0C to 150C. The reaction mixture was filtered through the Celite bed and washed with water (300 ml). N,N-dimethylformamide (100 ml) was added to the filtered solution at 1O0C followed by slow addition of isopropanol (4.5 L) in 4 hours to 5 hours at 50C to 1O0C. The mixture was stirred for 4 hours at O0C to 50C, filtered and washed with isopropanol (500 ml) and ethanol (200 ml) under nitrogen atmosphere. The solid was dried under reduced pressure at 4O0C to 45C to obtain the title compound.Yield: 45.0 g
(6R,7R)-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino}-3-(imidazo[1,2-b]pyridazin-1-ium-1-ylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate hemihydrochloride[ No CAS ]
[ 113981-44-5 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In acetone; at 15 - 20℃; for 1.0h;Product distribution / selectivity;
Polymorphic Form III of cefozopran hemihydrochloride (7.0 g) was suspended in acetone (70 ml) and hydrochloric acid (gas) was purged into the suspension. The reaction mixture was stirred at 150C to 2O0C for 60 minutes. The solid was filtered, washed with acetone (15 ml) and dried at 4O0C to 450C under reduced pressure to obtain the title compound.Chloride Content: 6.8% Yield: 6.O g
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