| 66.4% |
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To silylated 5-azacytosine (Example A-l) was added dichloromethane (1.5 L). The mixture was stirred for 10 minutes under nitrogen atmosphere at 25-30C to obtain a clear solution. The solution was gradually cooled to 0-5C. l ,2,3,5-Tetra-0-acetyl-P-D- ribofuranose (255.5 g, 0.8029 mol) was added in one lot at 0-5 C under nitrogen atmosphere. The mixture was stirred for 10 minutes at 0-5 C to obtain a clear solution. Stannic chloride (255.6 g, 0.9813 mol) was added drop-wise (addition was slightly exothermic) at < 10C over a period of 1 hour. The reaction mass was stirred for 5 hours at 0-5 C under nitrogen atmosphere.[00252] The progress of the reaction was checked by HPLC. 5 g of reaction mass was withdrawn and neutralized with saturated aqueous NaHC03 solution at 10C. The dichloromethane layer was separated and submitted for IPC-HPLC (In-Process-Control- HPLC). Once IPC had been met (5-azacytosine no more than 0.5% by HPLC), the reaction mass was transferred to a 5-L round bottom flask for work up.[00253] To the reaction mass was added dichloromethane (1.0 L) and sodium bicarbonate (800.0 g) at < 10C. Chilled water (1.0 L) was added drop-wise (exothermic) at < 10C over 30 minutes. The mixture was stirred for 30 minutes at < 10C. After 15-30 minutes, a white solid (tin oxide) settled at the bottom of the flask. The mixture was filtered through Hyflo, and washed with dichloromethane (0.5 L). The organic layer was separated at < 10C, and washed with water (0.75 L) at < 10C. The organic layer was washed with 10% EDTA disodium salt solution twice (150.0 g salt, 2 x 750 mL) and water once (1.0 L) at < 10C. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off at 40-45 C under atmospheric conditions, and further dried at 40-45C under vacuum (10-15 mmHg) to give a sticky foaming solid. To the residue was added methanol (200.0 mL) at 30-35C. The solvent was then distilled off at 40-45C under vacuum (10-15 mmHg), and degassed under vacuum for 30 minutes to afford 2',3',5'-triacetyl-5-azacytidine as a solid (315.0 g, white to off-white crystalline solid). The average output of 2',3',5'-triacetyl-5-azacytidine over multiple runs was about 305.2 g, with an average purity of about 83.7%>, and an average yield of about 77.2% (%> yield takes into account the HPLC purity of the product). Over five runs, the maximum yield of 2', 3 ',5 '-triacetyl-5-azacytidine was about 81.5% (% yield takes into account the HPLC purity of the product). Over five runs, the maximum HPLC purity of the product was about 87.8%>. The reaction conditions for the coupling and the deprotection steps were optimized by varying a number of parameters. The results are summarized in Table 1 below. Inexpensive and commercially readily available metallic Lewis acids, such as stannic chloride and ferric chloride, gave desirable yields for the coupling step. |
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With trifluorormethanesulfonic acid; In ethyl acetate; at 5 - 30℃;Product distribution / selectivity; |
Hexamethyldisilazane (94.5 ml_), ammonium sulfate (1.25 g) and 5- azacytosine (25 g) were placed into a clean and dry round bottom flask and stirred. The mixture was heated to reflux at 120-1340C and maintained for 2 to 3 hours. The mixture was distilled under vacuum to give a residue and it was allowed to cool to 25-300C. Ethyl acetate (250 ml_) was charged to the residue and stirred. 1 ,2,3,5- tetra-O-acetyl-beta-D-ribofuranose (67.4 g) was added and the mixture was cooled to 5-10C. Triflic acid (23.6 ml_) was slowly added over 10-30 minutes and the mixture was allowed to warm to 20-300C and stirred for 1 -2 hours. Ethyl acetate (125 ml_) and water (125 ml_) were added and stirred. The organic layer was separated, washed with 20% sodium chloride solution (125 ml_), and dried over sodium sulfate. The organic layer was distilled under vacuum at about 40 to 45C to give a residue of 2,3,5-tri-O-acetyl-5-azacytidine (50.0 g). |
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With trimethylsilyl trifluoromethanesulfonate; In acetonitrile; at 60 - 75℃; |
Compound A (20 g) and tetraacetyl ribose (20.2 g),Trimethylsilyl trifluoromethanesulfonate (0.15g)Mixed with acetonitrile (60 ml) in a three-necked flask.Raise the temperature to 60-75 C, stir the reaction for 6-7 hours, after the reaction is complete,The temperature was lowered to 10 to 40 C, and the insoluble matter was removed by filtration, and 300 ml of methanol was added thereto, and a methanol solution of sodium methoxide (25 ml, 30% by weight) was added dropwise at 10 to 30 C.After adding sodium methoxide solution, the pH of the reaction solution is 12-14, and the mixture is stirred for 3 to 4 hours.Filtration under reduced pressure gave a crude azacitidine 1, dried at 40 to 50 C to a constant weight of 17.8 g.Yield: 93.4%.Azacitidine crude 1 (19.8g) and DMSO (80ml) are mixed, heated to about 30-35 degrees, stirred for 1-2 hours, the solid is dissolved, and the insoluble matter is removed by filtration under reduced pressure at 30-35 C. Methanol (200 ml) was added to crystallize, stirred for 1 to 5 hours under reduced pressure, and dried under vacuum at 40 to 50 C to obtain crude azacitidine 2 (15 g). Yield: 75.8%.The crude azacitidine 2 (15 g) was added to absolute ethanol (150 ml), stirred at 10 to 30 C for 1 to 6 hours, filtered under reduced pressure, and dried at 40-50 C to obtain 13.5 g of aza cell extract. The HPLC purity was 99.98%. Yield: 90%. |
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