52% |
With 1-methyl-pyrrolidin-2-one; triethylamine; In ethanol; N,N-dimethyl-formamide; at 60 - 70℃; for 1h;Large scale; |
comprising the steps of: (1) In a clean glass kettle, 5 L of DMF, 5 L of N-methylpyrrolidone and 0.5 L of absolute ethanol, lkg of <strong>[106941-25-7]PMEA</strong> And 4.5kg of chloropentyl pivalate, stirring to 60 ~ 70 C, dropping 3 kg of triethylamine, 1 h after the drop is completed, and then reaction 2.5 After the hour, the reaction was detected by HPLC, and the amount of <strong>[106941-25-7]PMEA</strong> in the reaction solution was less than 0.5%, and the reaction was terminated. (2) 10 L of ethyl acetate was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour, filtered, and washed with 10 L of ethyl acetate The filter cake was washed with 10 L of a 20% sodium chloride solution, the aqueous phase of the washing solution was discarded, and the organic phase was washed with anhydrous Calcium chloride lkg dry 2 h, filter, remove the calcium chloride solid, the filtrate. (3) The filtrate was concentrated under reduced pressure at 45 C, and then 1L of chloroform was dissolved under stirring at 5 to 10 C, and the mixture was transferred to another A reaction kettle, in the 5 ~ 10 C dropping 12L methyl tert-butyl ether, 10-15 min after the white crystal precipitation, stirring crystallization 6-7 H, filter, 45 C vacuum drying <strong>[106941-25-7]Adefovir</strong> dipivoxil finished product 0.96kg: molar yield of 52%, by HPLC, the content of 99.7%, containing impurities <strong>[106941-25-7]Adefovir</strong> monoester 0.19%. The product is good crystal, easy to dry, good stability |
34.9% |
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 2h; |
A mechanical stirrer, reflux condenser and thermometer were installed in a 50 L dry reaction flask. (3.66 mol) of <strong>[106941-25-7]PMEA</strong> and 3.6 L of N-methylpyrrolidone (NMP) were added thereto in succession, followed by the addition of 2.2 kg (14.67 mol) of chloromethyl pivalate and triethylamine 1. lkg . After heating to 60 C for 2 hours, the mixture was cooled to room temperature and extracted three times with 20 L of isopropyl acetate. The filtrate was washed with water and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 5 L of acetone, With stirring, 25 L of isopropyl ether was slowly added to give a solid product, and stirring was continued for 5 hours, followed by filtration. (1/9, nu / nu). After adding the right amount of acetone to dissolve the filter cake, add appropriate amount of activated carbon, stir for 30 min and filter to the clean area crystallization tank, add isopropyl ether to crystallize completely, filter and use acetone / After sufficient washing, vacuum drying (50 C, 20 mmHg)To obtain 767 g of adefovir dipivoxil as an off-white powder with a purity of 99.1% and a total yield of 34.9%. |
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With triethylamine; In N,N-dimethyl-formamide; at 20 - 45℃;Industry scale; |
3600mNo. of N,N-dimethylformamide, 900g(3.3mol) of adefovir and 1608mNo.(11.52mol) of triethylamine were placed in a reactor in sequence, and 1665mNo.(11.52mol) of chloromethyl pivalate was added thereto at room temperature(20~25C), followed by stirring at 450C for 8 hours and at room temperature for 12 hours. 9000m£ of isopropyl acetate was added to the resulting reaction mixture and stirred at room temperature for 30 minutes. The suspension was filtered and the insoluble filtrate was washed with 1800mNo. of isopropyl acetate. The filtrate and the washed solution were combined and washed with 9000 m£ of water. The aqueous layer was extracted with 4500m£ of isopropyl acetate. The organic layers were combined, washed twice with each of 4500m£ of water, dried over 18Og of magnesium sulfate, and then concentrated under a reduced pressure to obtain 108Og of crude adefovir dipivoxil (yield 66%, chemical purity 85%). |
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With triethylamine; In dimethyl sulfoxide; at 40℃; for 5h;Product distribution / selectivity; |
Example 1: Preparation method of adefovir dipivoxil, 9-[2-[[bis{(pivaloyloxy)-methoxy}phosphinyl]methoxy]ethyl]adenine, represented by Formula 1 100 g of 9-[2-(phosphonomethoxy)ethyl]adenine ("adefovir") and 400 g of dimethyl sulfoxide (DMSO) were fed into a reactor. After 140 mg of triethylamine and 250 g of chloromethylpivalate were subsequently added thereto, the mixture was heated until a reaction temperature reached 40C and stirred for 5 hours. After the reaction temperature was lowered to 10C to 20C, 500 ml of dichloromethane and 1000 ml of distilled water were added thereto, followed by stirring for 5 minutes. Then, an organic layer was separated. |
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EXAMPLE-2Process for the Preparation of <strong>[106941-25-7]Adefovir</strong> Dipivoxil<strong>[106941-25-7]Adefovir</strong> (100 gm) was taken in a flask and to this a mixture of N,N-dimethylacetamide (225 ml) and ethyl acetate (75 ml) was added. To this triethyl amine (111 gm) and tetra butyl ammonium bromide (30 gm) was added and stirred at 25-35 C. for 1 hour. The temperature was raised to 54-56 C. To this chloromethyl pivalate (275.6 gm) was added and the reaction mass was cooled to 25-35 C. To the reaction mass ethyl acetate (400 ml) was added and filtered. The filtrate was taken into another flask and to this water was added. The ethyl acetate layer was separated and washed with purified water. The ethyl acetate layer was dried under anhydrous sodium sulphate and the ethyl acetate layer distilled under vacuum. To this methyl-tert butyl ether (300 ml) was added and the reaction mass was cooled to 0-5 C. This was washed with chilled ethyl acetate and MTBE mixture. The compound was suck dried to yield adefovir dipivoxil. |
22.8 g |
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; |
In a 1000 ml reaction flask, 30 g of adefovir was suspended in 150 ml of NMP, 30 g of triethylamine was added, 60 g of chloromethyl pivalate was added dropwise with stirring, and the temperature was raised to 50 C for 2 to 4 h. After completion of HPLC analysis of the reaction, ethyl acetate 330ml was added, and stirred for 2 hours to precipitate a white solid. White crystals were filtered, the filtrate was washed with 70ml of ethyl acetate, washed twice with 240 ml water, the organic liquid phase were combined, dehydrated by adding 100 g anhydrous sodium sulfate, filtered, and the ethyl acetate was recovered under reduced pressure. The residue after evaporation was dissolved in a mixed solution of acetone and isopropyl ether at room temperature, wherein the volume ratio of acetone to isopropyl ether was 1:8, and the mixture was stirred. Thereafter, the mixture was cooled to 0 C, and suction filtered under reduced pressure to give a white solid (25.5 g) of crude adefovir dipivaloyloxymethyl ester in a yield of 85.0%. (4) Refinement of adefovir dipivalyloxymethyl ester 25.5 g of the crude adefovir dipivoxil obtained in step 3 was dissolved in 51 ml of acetone, 1.2 g of activated carbon was added, the temperature was raised to 50-60 C, stirred for 0.5 hour, hot-filtered, then 200 ml of methyl tert-butyl ether was added, and the mixture was frozen to 0-5 C. The white product was precipitated at 5 C, and the mixture was centrifuged or filtered to obtain a white solid, which was dried under vacuum at 40 C to obtain a pure adefovir dipivoxil; 22.8 g of adefovir dipivoxil was obtained by NMR, and the HPLC content was 99.50%. |