| 92% |
Stage #1: (1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide With hydrogen; sulfur trioxide trimethylamine complex; triethylamine In water; isopropyl alcohol
Stage #2: tetrabutylammonium acetate In water; isopropyl alcohol |
4.4a
Example 4aTetrabutylammonium ([(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl]oxy}sulphonyl]oxidanide was prepared as described below.(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (10 g, 36.2 mmol, 1 eq) was mixed with sulfur trioxide trimethylamine complex (6.07 g, 43.44 mmol, 1.2 eq), triethylamine (1.3 ml, 18 mmol, 0.25 eq), palladium on carbon (0.8 g, 10% palladium, 50% water), isopropanol (50 ml) and water (50 ml). This mixture was treated with hydrogen until the reaction was deemed to be complete. The catalyst was removed by filtration and washed with water (20 ml). The combined filtrates were washed with n-BuOAc (70 ml, 20 ml) before a solution of tetrabutylammonium acetate (54.5 mmol) in water (20 ml) was added. The product was extracted with dichloromethane (100 ml, 50 ml) and solvent swapped into 4-methyl-2-pentanone, before filtering, washing and drying to yield a white crystalline solid (16.9 g, 92%).1H NMR (400 MHz, CDCl3) δH 1.00 (12H, t), 1.45 (8H, m), 1.67 (9H, m), 1.87 (1H, m), 2.16 (1H, m), 2.37 (1H, dd), 2.87 (1H, d), 3.31 (9H, m), 3.91 (1H, d), 4.33 (1H, s), 5.79 (1H, s), 6.67 (1H, s). |
| 85% |
Stage #1: (1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide With formic acid; palladium on activated charcoal; ammonium formate In isopropyl alcohol at 35℃;
Stage #2: tetrabutylammonium acetate In water at 20℃; for 3h; |
5 Example 5 Preparation of (Compound K) ([(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo)[3,2,1]-oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt:
Isopropanol (9000 ml) was added to the reaction flask, and compound J (600.0 g), palladium on carbon (60.0 g), ammonium formate (68.7 g) and formic acid (200.5 g) were added.The reaction temperature was controlled at 30 ° C to 35 ° C for 2 to 3 hours, and the J reaction was completely detected by HPLC, followed by suction filtration and washing.Triethylamine (55.0 g) and trimethylamine trioxide (424.6 g) were added to the filtrate.The temperature is controlled at 30 ° C to 35 ° C, and the reaction is stirred for 3 to 4 hours.An aqueous solution of 35% tetrabutylammonium acetate (821.4 g) was added thereto, and the reaction was stirred at room temperature for 3 hours, and the reaction liquid was concentrated to 10 kg.Dichloromethane (3.6 kg X2) was added to the concentrated reaction mixture for 2 times. After phase separation, the organic phase was concentrated under vacuum at 40 to 50 ° C to give an oil.After adding 1800 ml of methyl isobutyl ketone, the mixture was subjected to crystallization, suction filtration, washing and drying to obtain 938.4 g of the title compound K. The yield was 85.0%, the purity was 99.7%, and the single impurity was <0.1%. |
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