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EXAMPLE 2: Preparation of Tenofovir (using sodium hydride and magnesium chloride). To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged dimethyl formamide (500 ml) and 9-[2-(R)-(hydroxy)propyl] adenine of formula III (100 gms) at temperature 20C to 35C. Cooled to 0C to 5C and added sodium hydride (41.5 gms) and stirred for 60 minutes at same temperature. Heated to 25C to 30C and added magnesium chloride (56 gms) and stirred for 2 hours at 25C to 30C. To the reaction mass added diethyl p-toluene sulfonyloxy methyl phosphonate (225 gms) at 25C to 30C and stirred for 1 hour at same temperature. Heated to 70C to 75C and stirred for 4 hours at same temperature. Reaction was monitored by HPLC and observed 75% of the reaction product formed. Cooled the reaction temperature to 25C to 30C and added methanol (20 ml) and then solvent was removed from the reaction mixture by distillation under vacuum at below 70C to obtain (R)-9-[2-(diethylphosphono methoxy) propyl] adenine of formula II as thick residue.Cooled the resultant residue to 25C to 35C and charged aqueous hydrobromic acid (524ml). Heated to 90C to 95C and stirred for 5 hours at same temperature. After completion of the reaction, the reaction mass was cooled to 25C to 30C and stirred for 30 minutes at same temperature. Filtered the salts formed and washed the salts with methylene chloride (300 ml). Taken filtrate and separated methylene chloride layer from the aqueous layer and then adjusted the aqueous layer pH to 2.5 to 3 with 50% sodium hydroxide solution at 20C to 30C. Cooled the solution to 0C to 5C and stirred for 4 hours. Filtered the precipitated product and washed with chilled water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product charged water (1200 ml), heated to 95C to 100C and stirred for 30 minutes at same temperature. Cooled to 25C to 30C and then to 0C to 5C and stirred for 4 hours. Filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70C to 75C under reduced pressure to provide the title compound. Yield: 85 gms. HPLC purity: 98.7% |
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EXAMPLE 1 :Preparation of Tenofovir (using sodium amide and magnesium chloride).To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged dimethyl formamide (400 ml) and 9-[2-(R)- (hydroxy)propyl] adenine of formula III (100 gms) at temperature 20C to 35C. Cooled to 0C to 5C and added sodium amide (40.4 gms) at temperature 0C to -10C and stirred for 30 minutes at same temperature. Heated to 25C to 30C and stirred for 2 hours at same temperature. Added magnesium chloride (49.2 gms) and stirred for 1 hour at 25C to 30C. To the reaction mass was charged toluene (300 ml) and heated to 50C to 55C and stirred for 4 hours at same temperature and then again heated to 75 C to 80C. At this temperature added diethyl p-toluene sulfonyloxy methyl phosphonate (250 gms) and stirred for 2 hours at same temperature. After completion of the reaction, the solvent was removed from the reaction mixture by distillation under vacuum at below 70C to obtain (R)-9-[2-(diethylphosphono methoxy) propyl] adenine of formula II as thick residue. Cooled the resultant residue to 25C to 35C and charged aqueous hydrobromic acid (650 ml). Heated to 90C to 95C and stirred for 2 hours at same temperature. After completion of the reaction, the reaction mass was cooled to 25C to 30C and stirred for 30 minutes at same temperature. Filtered the salts formed and washed the salts with methylene chloride (300 ml). Taken filtrate and separated methylene chloride layer from the aqueous layer and then adjusted the aqueous layer pH to 2.5 to 3 with 50% sodium hydroxide solution at 20C to 30C. Stirred the solution for 1 hour at 20C to 25 C and cooled to 0C to 5C and then stirred for 4 hours. Filtered the precipitated product and washed with chilled water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product charged water (900 ml), heated to 90C to 95C and stirred for 30 minutes at same temperature. Cooled to 25C to 30C and then to 0C to 5C and stirred for 4 hours. Filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70C to 75C under reduced pressure to provide the title compound.Yield: 90 gms.[0076] HF-LC purity: 98.5%[0077] HPA: Not detected[0078] The XRPD is set forth in Figure- 1 |
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With magnesium 2-methylpropan-2-olate; In 1-methyl-pyrrolidin-2-one; at 25 - 75℃; |
EXAMPLE 2Preparation of TenofovirN-methyl-2-pyrrolidone (25 gm) was taken along with toluene (150 gm) into a reaction vessel. 1-(6-amino-purin-9-yl)-propan-2-ol (100 gm); toluene-4-sulfonic acid diethoxy phosphoryl methyl ester (200 gm) and magnesium ter-butoxide (71.2 gm) were also taken at 25-35 C. Temperature was raised to 74-75 C. and maintained for 5-6hrs. After completion of reaction, acetic acid (60 gm) was added and maintained for 1 hr. Later aq.HBr (332 gm) was taken and heated to 90-95 C. After reaction completion, salts were filtered and filtrate was subjected to washings with water and extracted into methylene dichloride. Later pH was adjusted using CS lye below 10 C. Tenofovir product was isolated using acetone.Yield: 110 gm. |
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Preparation of Tenofovir using dimethyl formamide-hydrochloric acid complex. To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel dimethyl formamide (200 ml), 9-[2-(R)- (hydroxy)propyl] adenine (HP A) (100 gms) and Magnesium t-butoxide (72gms)were charged at temperature 20C to 35C and stirred for 30 minutes at same temperature. Diethyl p-toluene sulfonyloxy methyl phosphonate (225gms) (DESMP) was added and temperature was raised to 75 C to 80C and stirred for 2 hours at same temperature. Reaction mass was cooled to 0C to 5C and dry hydrochloric acid gas was passed for 5 hours. Reaction mass was heated to 90C to 95C and maintained for 4 hours. After completion of the dealkylation and monitored by HPLC, the solvent was removed completely under vacuum below 70C and water (400 ml) was added to the resultant residue at temperature 60C to 65C. Adjusted pH of the reaction mass to about 1 with Concentrated HQ. Filtered the salts formed and washed the salts with 10% HC1 solution. Filtrate was taken and pH was adjusted to about 2.5 with 50% NaOH solution and the reaction mass was cooled to 0 to 5C. Filtered the precipitated product and washed with water (100 ml) and then washed with chilled acetone (100 ml). To the resultant wet product water (800 ml) was charged and heated to 90C to 95C. Temperature was cooled to 25 C to 30C and filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70C to 75C under reduced pressure to provide the title compound. Yield: 82gms. HPLC purity: 99.2% |
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EXAMPLE 2 Preparation of Tenofovir (Using Sodium Hydride and Magnesium Chloride) To a clean 3-necked 2 L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged dimethyl formamide (500 ml) and 9-[2-(R)-(hydroxy)propyl]adenine of formula III (100 gms) at temperature 20 C. to 35 C. Cooled to 0 C. to 5 C. and added sodium hydride (41.5 gms) and stirred for 60 minutes at same temperature. Heated to 25 C. to 30 C. and added magnesium chloride (56 gms) and stirred for 2 hours at 25 C. to 30 C. To the reaction mass added diethyl p-toluene sulfonyloxy methyl phosphonate (225 gms) at 25 C. to 30 C. and stirred for 1 hour at same temperature. Heated to 70 C. to 75 C. and stirred for 4 hours at same temperature. Reaction was monitored by HPLC and observed 75% of the reaction product formed. Cooled the reaction temperature to 25 C. to 30 C. and added methanol (20 ml) and then solvent was removed from the reaction mixture by distillation under vacuum at below 70 C. to obtain (R)-9-[2-(diethylphosphono methoxy)propyl]adenine of formula II as thick residue. |
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With magnesium 2-methylpropan-2-olate; In dimethyl sulfoxide; at 70℃; |
Example I (Stage 2a using MTB in DMSO) A 0.5M solution of HPA 6 (1 g, 5.18 mmol, 1.0 eq) in DMSO (10.3m1) was prepared. MTB (2.65 g, 15.53 mmol, 3.0 eq) was added to the solution at ambient temperature. The resuJting slurry was heated to 70 C and DESMP (2.5 g, 7.76 mmol, 1.5 eq) was added dropwise over 10-15 mm. The resulting mixture was stirred at 70 C for 3 h after which time LCMS showed - 90% conversion to product. LCMS after 16 h indicated - 96% conversion (both regioisomers). LCMS retention time 3.403 mm, mlz 344.2 [M +1]. |
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To a clean 3-necked 2L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel dimethyl formamide (200 ml) and 9-[2-(R)-(hydroxy)propyl] adenine (HPA) (50 gms) were charged at temperature 20 C. to 35 C. Reaction mass was cooled to 0 C. to 5 C. and sodium amide (20.2 gms) was added at temperature 0 C. to -10 C. and stirred for 30 minutes at same temperature. Magnesium chloride (24.6 gms) was added and stirred for 1 hour at 25 C. to 30 C. To the reaction mass toluene (150 ml) was charged and heated to 75 C. to 80 C. Diethyl p-toluene sulfonyloxy methyl phosphonate (125 gms) (DESMP) was added and stirred for 2 hours at same temperature. Reaction mass was cooled to 20 C. to 25 C. and acetic acid was added to obtain the phosphonate ester compound solution. [0088] In another 3-necked 3 L round bottom flask trimethylamine. HCl (120 gms) and aluminium chloride (138 gms) were added at 20 C. to 25 C. and heated to 100 C. and stirred for 15 minutes to obtain the trimethylamine.HCl-aluminium chloride complex. To the trimethylamine.HCl-aluminium chloride complex, phosphonate ester compound solution obtained above was added at temperature 95 C. and stirred for 5 hours at 90 C. to 95 C. After completion of the dealkylation, monitored by HPLC, the solvent was removed completely under vacuum below 70 C. and water (200 ml) was added to the resultant residue at temperature 60 C. to 65 C. Filtered the salts formed and washed the salts with methylene chloride (150 ml). Filtrate was taken and methylene chloride was separated then pH was adjusted the aqueous layer to 2.5 to 3 with 50% sodium hydroxide solution at 20 C. to 30 C. Filtered the precipitated product and washed with water (50 ml) and then washed with chilled acetone (50 ml). To the resultant wet product water (400 ml) was charged and heated to 90 C. to 95 C. Temperature was cooled to 25 C. to 30 C. and filtered the product and washed with chilled water (50 ml) and then washed with chilled acetone (100 ml). The wet product was dried at 70 C. to 75 C. under reduced pressure to provide the title compound. [0089] Yield: 30 gms. [0090] HPLC purity: 98.9%. |
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To the reaction vessel, 100 g of N, N-dimethylformamide was added,(R) -9-2- (hydroxypropyl) adenine,8 g of magnesium t-butoxide and 90 g of diethyl p-toluenesulfonyloxymethylphosphonate,Stirring,Heated to 90 ~ 95 ,Stirring for 8 hours,The reaction was terminated to give a reactant.Cooled to room temperature,Adding glacial acetic acid,The pH was adjusted to pH 6.5-7.5. Add the appropriate amount of dichloromethane, reflux 5 hours,Separation and extraction of methylene chloride layer, filtration, dichloromethane washing, combined filter fluid, vacuum distillation, was thick. The molar ratio of (R) -9-2- (hydroxypropyl) adenine and magnesium t-butoxide was 1: 0.6.90 |
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1) at 20 ~ 35 conditions, with stirring, 100 grams of HPA was suspended in 300 ml N, N- dimethyl formamide; at 0 ~ 5 , was added 116 g of potassium t-butoxide, stirred for half an hours; 25 ~ 30 , stirred for 2 hours, 49.2 g of magnesium chloride was added, stirred for 1 hour;After the mixture 2) in step 1) was incubated at 60 deg.] C obtained in 2 hours, and warmed to 75 ~ 80 , was added after 200 g DESMP at 75 ~ 80 , stirred for 5 hours;3) The reaction was incubated at 70 deg.] C the solvent was distilled off under reduced pressure, cooled to 25 ~ 35 , aqueous hydrobromic acid was added 600 ml, 90 ~ 95 incubated for 5 hours;4) Step 3) the resulting reaction was cooled to 25 ~ 35 , stirred for half an hour, filtered; the filter cake was washed with 300 ml of methylene chloride;5) After stirring for 1 hour and the filtrate layers were separated; the aqueous layer was neutralized with 50% sodium hydroxide to pH 2.5 ~ 3.0, at 20 ~ 25 conditions, for half hour; 0 ~ 5 , stirred for 4 hours;6) The filter cake was dispersed in 900 ml of water, stirred at 90 ~ 95 1 hour, cooled to room temperature, and then cooled to 0 ~ 5 stirred for 4 hours;7) and the filter cake washed with 50 ml of cold water, then washed with 100 ml of cold acetone, 70 ~ 75 dried to obtain 109 g tenofovir, yield 73%. |
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(R) -hydroxypropyladenine, 47 g of DMF (N, N-dimethylformamide) and 6.2 g of magnesium tert-butoxide were added to a four-necked flask in a dry system, and the temperature was raised to 70 ± 5 C After the temperature was maintained for 1 h, 21 g of diethyl p-toluenesulfonyloxymethylphosphonate (DESMP) was added dropwise and the temperature was maintained for 4 h. The sample was sampled by HPLC. When the HPA was less than 1%, the heating was stopped and the temperature was lowered to below 20 C , And 4.05 g of TsOH · H was added dropwise2After the dropwise addition, the temperature was raised to 80 C, DMF was distilled off under reduced pressure, 350 g of ethyl acetate was added, the mixture was filtered while hot, and the filtrate was distilled to distill off the acetic acid ethyl acetate Ester, to give PMPA diethyl ester |
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Intermediate (II) (36.00g) in dry DMF and three-necked flask (240ml) was dissolved with stirring at 0 C plus The lithium tert-butoxide 18.37g, then at room temperature for 2h, then added slowly (diethoxy phosphono) methyl-4-methylbenzenesulfonate 60.08g, 0 C the reaction 12h, then at the same temperature was added lithium tert-butoxide 9.19g, after stirring for 1h, a solution of (diethoxy phosphono) Methyl-4-methylbenzenesulfonate (30.04g), stirred 5H; lithium t-butoxide was added 4.5g, stirred for 1h, then a solution of (diethoxy phosphine Acyloxy) methyl-4-methylbenzenesulfonate 15.02g, same temperature for 12h, to the reaction system was slowly added acetic acid to adjust pH to ~ 6 7The mixture was concentrated under reduced pressure to give a pale yellow oil, crude yield quantitative terms, directly into the next reaction (Example 5). |
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In N,N-dimethyl-formamide; at 60℃; |
In a 1000 ml three-necked flask, 100 g of adenine, 1.2 g of sodium hydroxide, 84 g of R-carbon-1,2-propanediol and 700 ml of DMF were added and the temperature was raised to 130 C with stirring. The reaction mixture was cooled to 25 C, 8 g of lithium hydride was added, and then heated to 70 C. The reaction was allowed to react for 2 hours and then cooled to room temperature,300 g of p-toluenesulfonyloxymethyl phosphate was added and the reaction mixture was maintained at 60 C until TLC showed a complete reaction. The reaction mixture was concentrated in vacuo at a temperature not exceeding 80 C, 500 ml of water was added and the mixture was stirred and the aqueous solution was continuously extracted with methylene chloride. The dichloromethane extract was combined and the extract was concentrated in vacuo at not higher than 80 C to give a viscous orange (R) -9- [2- (diethylphosphonoylmethoxy) propyl] adenine in the orange oil containing 65% (Diethylphosphonoylmethoxy) propyl] adenine crude can be used directly in the subsequent reaction without purification. |
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Adding glass autoclave convenient replacement adenine (7.5 kg, 55 . 50mol), R-propylene carbonate (8.25 kg, 80 . 81mol), DMF (30 kg, 410 . 45mol) and NaOH (0.23 kg, 5 . 75mol), stirring the mixture at room temperature for 10 minutes, the system, to start-up of heating 120-130C, thermal reaction, every 1 hour detecting TLC, the reaction is complete, to stop the reaction, cooling to 45-60C, joins uncleding Chunmei in the reaction liquid (7.4 kg, 43 . 39mol), then heating to 60-80C, start dropping paratoluene sulfonyloxy phosphoric acid diethyl ester (30 kg, 93 . 08mol), add reaction is preserved after the 6-hour, tracking of the reaction, to be (R) - 9 - (2-hydroxy-propyl) adenine after the reaction is complete, cooling to 60 C, plus 4.5 kg acetic acid, stirring 10 minutes, to concentrated under reduced pressure, to obtain R-9 [(diethyl phosphinylidyne methoxy ) propyl] purine, cooling to 50 C, by adding the mass concentration is 30% hydrochloric acid of 37.5 kg, stirring to dissolve, cooling to 15 C the following stirring 1 hour, a large number of solid precipitation, filtration of the solid, the filtrate in the 85 C sustained-access access 6kgHCL gas, reaction 18 hours, to after the reaction is complete, reaction solution is concentrated under reduced pressure to the slurry, by adding 45 kg water, stirring to dissolve, PH value is adjusted with ammonia water to the 3.0-3.5, obtained crude PMPA, filtering out the solid, using 10 times the crystallization is provided, to filter out solid and atmospheric drying is 9 kg of refined PMPA, ? 99% purity, the yield is 120%. |
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With magnesium 2-methylpropan-2-olate; In N,N-dimethyl-formamide; at 60 - 70℃;Inert atmosphere; |
In sequence under nitrogen protection, DMF (50g), R-propylene carbonate (17.2g, 168mmol), adenine (20g, 148mmol), and NaOH (0.2g, 5mmol), heating to 125-135C, and thermal insulation reaction 6-8 hours; cooling to 60-70C, ding Chunmeijoins uncle (20.3g, 119mmol), then dropwise DESMP (64g, 199mmol), the drop finishes, 60-70 C insulation reaction 6-8 hours, esterification reaction is over, cooling, adds the second grade acid is neutralized, decompression does thickly DMF (80 C, the [...] 5mmHg), added 48% hydrobromic acid of (160g) dissolves uniform, heating to 90-100 C insulation reaction 3-5 hours, cooling to 20-25C, then adding 40% NaOH solution regulating PH value to 3.0, cooling to 5-8 C crystallization 3 hours, filtered, to crude PMPA 48g, PMPA crude in 20-25 C with 5% hydrochloric acid (140g) dissolved, then using 5% sodium hydroxide (175g) adjusting PH value to 2.5, cooling to 0-5C, thermal insulation 1h, filtering, washing two times with water, 100 C -105 C drying to obtain the finished product 24.7g, HPLC purity 99.6%. (Molar yield to adenine as 58%). |
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With lithium tert-butoxide; In N,N-dimethyl-formamide; at 30 - 35℃; |
HPA 40g (0.21 mol) To 200 ml of dimethylformamide (DMF) After dissolving, 25.2 g (0.315 mol, 1.5 Equiv.) Of lithium t-butoxide was added and suspended. (0.325 mol, 1.5 Equiv.) Of diethyl-p-toluenesulfonyloxy methanephosphonate (DEPTSMP) was added in two portions at a temperature of 30 to 35 C for 30 minutes, The reaction progress was confirmed by TLC and HPLC (takes 12 hours).After the reaction was completed, the reaction mixture was cooled to 20 C, and glacial acetic acid was added thereto to adjust pH to 6-6.5. 1,000 ml of ethyl acetate was added thereto, and the mixture was heated to 50 to 60 C, which was then cooled to 40 C and filtered. The reaction byproduct lithium inorganic residue was added to 500 ml of ethyl acetate and stirred. After filtration at the same temperature to remove the inorganic matter, the organic solvents were combined, washed twice with 100 ml of cold distilled water at 10 C or less, and washed with 50 ml of saturated sodium chloride solution After the organic layer was dehydrated with anhydrous sodium sulfate, the organic layer was vacuum-distilled to obtain terpovir ester (DEPMPA). 300 ml of toluene was added to the residue (DEPMPA), and the mixture was distilled under reduced pressure to remove DMF and ethyl acetate as impurities. The residue was distilled under reduced pressure with 300 ml of cyclohexane. Ethyl acetate and DMF were again removed by distillation. Decomposition reaction was carried out. |
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With magnesium 2-methylpropan-2-olate; In 1-methyl-pyrrolidin-2-one; at 65℃; for 16.5h;Large scale; |
1. NMP was cooled to room temperature and added to the reactor. 2000 g of TNF-SM, 3500 g of magnesium tert-butoxide, Mechanical mixing evenly heated to 65 deg C, 30 g of diethyl-((p-toluenesulfonyl)oxy)methylphosphonate was added dropwise over 30 minutes, After 16 h of reaction, the mixture was allowed to cool to room temperature. To the reaction solution was added acetic acid, Adjust the reaction system pH 7 or so. The reaction solution was poured into 65 L of ethyl acetate under vigorous stirring and stirring was continued for half an hour, Filter, The filter cake was added to 30 L of dichloromethane, Stirring for half an hour, filter. The filter cake was beaten with 20 L of dichloromethane, Take care. Combine organic phase, 30 C under reduced pressure, To be quickly concentrated dry after heating to 60 deg C, Concentrated to dry. Get golden yellow liquid, This is a NMP solution of TNF-2. |
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With magnesium alkoxide; at 60 - 80℃;Inert atmosphere; |
Step S2 in, the condensation reaction is carried out under oxygen free conditions, in order to magnesium alkoxide as catalyst, the reaction temperature is 60 - 80 C. The states the magnesium alkoxide is selected from C1 - C4 of the mellow magnesium salt compound; said R - 9 - (2 - hydroxy-propyl) adenine and magnesium alkoxide of the feeding molar ratio of 1: 0.5 - 1.5. |
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7.25 g (0.0375 mol) of <strong>[14047-28-0](R)-9-[2-(hydroxy)propyl]adenine</strong>(HPA) Dimethylformamide (73 mL) was added to a 250 mL three-necked round-bottom flask and stirred at 75 C After the temperature was elevated, magnesium octan-2-olate (0.15 mol) synthesized in Example 1 was added while maintaining the temperature at 75C ,Followed by stirring at 75C for 1 hour. 30.2 g (0.0938 mol) of diethyl rho-toluenesulfonyloxymethylphosphonate (DESMP) was added at the same temperature, and the mixture was stirred at 80 C for 3 hours.After cooling to 25 C, the layer was separated and the upper layer was discarded and 108 mL of a saturated aqueous sodium chloride solution was added to the lower layer and stirred for 10 minutes. The filtrate was filtered through celite, and the filtrate was extracted three times with 73 ml of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate (7.3 g) and concentrated under reduced pressure to obtain (R)-9-[2-(diethylphosphinoMethoxy)propyl]denine (DPPA). |
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With calcium hydride; magnesium 2-methylpropan-2-olate; In N,N-dimethyl-formamide; at 30 - 35℃; |
Method of Using a Composite Catalyst of Magnesium t-Butoxide and Calcium Hydride and an Ion-Exchange Resin) 40 g (0.21 mol) of <strong>[14047-28-0](R)-9-(2-hydroxypropyl)adenine</strong> (HPA) was dissolved in 200 ml of dimethylformamide (DMF), and 143.2 g (0.84 mol, 4.0 eq.) of magnesium t-butoxide and 4.42 g (0.105 mol) of calcium hydride as a catalyst were added to make a suspension. While the reaction temperature was maintained at 30 to 35 C., 100 g (0.325 mol, 1.5 eq.) of diethyl-p-toluene sulfonyloxymethyl phosphonate (DEPTSMP) was added dropwise for 2 hours. With 5 or more hours of agitation at 80 C., the progress of the reaction was estimated through TLC and HPLC (taking 7 hours). After the completion of the reaction, acetic acid was added dropwise at 20 C. to control the pH value between 6 and 6.5 1,000 ml of ethyl acetate was added to the reactant solution, which was then heated up to 50 to 60 C., cooled down to 40 C. and subjected to filtration. The inorganic residue was additionally extracted cation with 500 ml of ethyl acetate and filtered at the same temperature, removing inorganic substances. After addition of an organic solvent, the solvent was separated under reduced pressure at 70 C. or below. The residual solution thus obtained was cooled down to 20 C. or below and subjected to separation using 1,000 ml of ethyl acetate and 100 ml of cold purified water. The organic layer separated was washed twice with 100 ml of cold water and then with 50 ml of a saturated saline solution (sodium chloride solution), dehydrated with anhydrous sodium sulfate, and separated under reduced pressure to obtain tenofovir ester (DEPMPA). 300 ml of toluene was added to the residue to eliminate the remaining DMF and ethyl acetate under reduce pressure. Subsequently, 300 ml of cyclohexane was added, and distillation was performed under reduced pressure to eliminate ethyl acetate and DMF. The residual solution, DEPMPA was then subjected to a dealkylation reaction, that is, hydrolysis. |
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100 g of 9- (2-hydroxypropyl) adenine (HPA) and 78.9 g of 0.6 molar equivalent of LiAlH (t-BuO) 3 as a solid are dissolved in 400 mL of DMSO. The reaction solution was stirred at a temperature of 25 to 30C for 20 minutes and after adding 83.4 g of 0.5 molar equivalent of DESMP (Diethyl P-toluene Sulfonyloxy Methyl Phosphonate, (C2H5O)2P(O)CH2OTs), the mixture was heated to 70 to 75 and stirred. After stirring for 3 hours, 78.9 g of 0.6 molar equivalent of LiAlH (t-BuO) 3 and 83.4 g of DESMP 0.5 molar equivalent were added and stirred for 3 hours.Further, 39.4 g of 0.3 mol equivalent of LiAlH (t-BuO) 3 and 0.33 g of 0.2 mol equivalent of DESMP were added and the reaction was terminated when the residual amount of HPA reached 15% or less. A dilute aqueous hydrochloric acid solution was added to adjust the pH to 6-7 and the reaction solution was concentrated at a temperature of 60 to 65 for 1 hour. Alcohol produced during the reaction was removed. 3 L of brine and 3 L of dichloromethane added to the reaction solution obtained by concentration and insoluble solid produced by stirring is removed by filtration and extracted to obtain only the organic layer. 1 L of Brine was added to the organic layer and extracted to obtain an organic layer and after adding anhydrous sodium sulfate and stirring and filtering, (R) -9- [2-diethylphosphonomethoxy] propyl] adenine, which is a yellow oil, is obtained by concentrating at a temperature of 60 to 65 C for 3 hours. (Yield is about 60 to 65%, and the purity is usually 70 to 85%.). It was confirmed that the yield was remarkably improved in the case of this example, as compared with the case where lithium alkoxide dissolved in a solvent was used instead of the solid LiAlH (t-BuO) 3. |
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With sodium sulfate; sodium t-butanolate; In toluene; at 80 - 85℃; for 7h; |
(4) adding a catalyst, 9-(2-hydroxypropyl)adenine, a third organic solvent, anhydrous sodium sulfate to the reactor,Warmly add diethyl p-toluenesulfonyloxymethylphosphonate, heat to 80-85 C, and keep the reaction for 7 h.After the reaction is completed, the mixture is filtered, and the filtrate is concentrated under reduced pressure to dryness to obtain tenofovir diester; the catalyst is potassium t-butoxide;The third solvent is toluene;The 9-(2-hydroxypropyl) adenine and the diethyl p-toluenesulfonyloxymethylphosphonate,The catalyst has a molar ratio of 1:1.3: 0.8; the 9-(2-hydroxypropyl) adenine and the third organic solvent,The weight ratio of the anhydrous sodium sulfate is 1:10:0.6; |
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With magnesium 2-methylpropan-2-olate; In 1-methyl-pyrrolidin-2-one; at 70℃; for 7h; |
Into a solution of 2 (90.0 g, 0.47mol) of N-methyl-2-pyrrolidone (450mL) added magnesium tert-butoxide (160.3 g, 0.94mol), and then heated at 70 C. Compound 3 (195.2 g, 0.61mol) was added drop-wise to the stirred mixture. The reaction was detected by TLC. After stirring for about 7 hours, the reaction is completed. The mixture was cooled at ambient temperature and the pH was adjusted to 6 with acetic acid, and then diluted with ethyl acetate (2000mL). The mixture was stirred and heated at 50 C to precipitate a magnesium salt. After stirring for about 30 minutes, the mixture was cooled and the precipitate was filtered. The filter cake was washed with ethyl acetate, and all the filtrates were combined and concentrated. Finally obtained light yellow liquid. The crude product (4) was used directly in the next step without further purification. |
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With magnesium 2-methylpropan-2-olate; In 1-methyl-pyrrolidin-2-one; at 70 - 79℃;Large scale; |
S01 etherification: 5 kg of (R)-9-(2-hydroxypropyl) adenine was added sequentially to the reaction vessel.20 L of N-methylpyrrolidone, slowly adding 7.5 kg of magnesium t-butoxide with constant stirring, and heating was started.After raising the temperature to 70 C, slowly add 10 kgP-toluenesulfonyloxymethyl phosphate,After about 30 minutes, the reaction temperature was maintained at about 79 C for continuous reaction.The reaction is stopped after the reaction of (R)-9-(2-hydroxypropyl) adenine is completed,Naturally cooled to room temperature; acetic acid was added to the system and the pH was adjusted to 7.0 with stirring.The reaction system was stirred to clarify; then the above reaction solution was slowly added to 150 L of ethyl acetate under rapid stirring.Solid precipitated, stirred, and centrifuged; the filter cake was beaten with 20 L of dichloromethane, and centrifuged.The filtrate was concentrated under reduced pressure at 50 C without distillation. The residue was added to 5 L of cyclohexane and concentrated to a fraction.get(R) N-methylpyrrolidone solution of 9-(2-phosphonomethoxypropyl)adenine di(ethyl) ester. |
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Step 4. (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine: In a reactor containing an inert atmosphere, for example nitrogen, adenine (1.0 kg),A mixture of sodium hydroxide (11.8 g), (R) -1,2-propylene carbonate (0.83 kg), and N, N-dimethylformamide (6.5 kg) was treated with about 0.5% area normalized HPLC, Indicating that the adenine remained unresolved until the reaction was completed,Heat to 130 C (typically about 125-138 C) for about 18-30 hours. The resulting mixture is cooled to about 25 C. (typically about 20 to 30 C.) and contains a Stage I intermediate, (R) -9- (2-hydroxypropyl) adenine, It can precipitate at this point. After cooling, lithium t-butoxide (3.62 kg), 2.0 M in tetrahydrofuran was added to stage I intermediate to produce the lithium salt of (R) -9- (2-hydroxypropyl) adenine in a mild exothermic reaction . The slurry was treated with diethyl p-toluenesulfonyloxymethyl phosphonate (1.19 kg) and the mixture was heated to a temperature of about 32 C. (typically about 30 to 45 C.) and heated for at least about 2 hours (Typically about 2 to 3 hours) Meanwhile, the mixture becomes uniform. Further diethyl p-toluenesulfonyloxymethylphosphonate (1.43 kg) is added and the mixture is heated at a temperature of about 32 C. (typically about 30-45 C.) for at least about 2 hours (typically about 2- 3 hours). Further lithium t-butoxide (0.66 kg), 2.0 M in tetrahydrofuran and diethyl p-toluenesulfonyloxymethylphosphonate (0.48 kg) were added two more times and after each time the mixture was added at a temperature of about 32 C. for at least about 2 hours Stir. Completion of the reaction is monitored by indicating that area normalized HPLC, if necessary, shows only 10% residual Stage I intermediate. If the reaction is incomplete, additional lithium t-butoxide (0.33 kg), 2.0 M in tetrahydrofuran and diethyl p-toluenesulfonyloxymethylphosphonate (0.24 kg) are added and the reaction mixture is heated at a temperature of about 32 C. Maintain reaction completion by maintaining for at least about 2 hours. The mixture is then cooled to about 25 C (typically about 20-40 C) and then glacial acetic acid (0.5 kg) is added. The resulting mixture is concentrated in vacuo at a final maximum mixture temperature of about 80 C., under a vacuum of about 29 inches Hg (in Hg). The residue is cooled to about 50 C. (typically about 40-60 C.) and water (1.8 kg) is added and the reaction is rinsed into additional water (1.8 kg). The solution is continuously extracted with dichloromethane (about 35 kg) for 12 to 48 hours and periodically glacial acetic acid (0.2 kg) is added to the aqueous phase after about 5 hours and about 10 hours after the continuous extraction time. Completion of extraction can be achieved by showing that the area-normalized HPLC shows that the residual amount of (R) -9- [2-diethylphosphonomethoxy) propyl] adenine in the aqueous phase is only about 7% It is confirmed. The combined dichloromethane extracts are first concentrated at atmospheric pressure and then in vacuo at extraction temperature at a temperature of only about 80 C. to give the title compound as a viscous orange oil. The title compound yield is about 40-45% by weight (normalized HPLC) and its purity is typically 60-65% by area normalized HPLC. The actual weight of the title compound after concentration is approximately 1.6 times the stoichiometric amount (ie, 3.8 times the expected yield). The additionally observed weight is due to impurities and / or solvents remaining after continuous extraction and concentration. |
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With magnesium 2-methylpropan-2-olate; In 1-methyl-pyrrolidin-2-one; at 25 - 70℃; for 4h; |
Add 40.00 g (0.207 mol) of intermediate (II) to a dry three-necked flaskAnd N-methylpyrrolidone (NMP) (160ml) stirred and dissolved,Join at 25oCMagnesium tert-butoxide70.00g (0.414mol),Then warm up to 70oC,Join slowly(diethoxyphosphonyl)methyl-4-methylbenzenesulfonate100.00g (0.311mol),Constant temperature reaction at 70 C for 4 h,After cooling to 20 ± 5 C,Slowly adding 36.75g (0.612mol) of acetic acid to the reaction system to adjust the pH to 6-7.Keep the temperature at 15~25 C,To the mixture was added 900 ml of ethyl acetate.Stir for 30 min, let stand, and pour off the supernatant.The filter cake was placed in a bottle and 300 ml of ethyl acetate was added and stirred at 15 to 25 C for 30 min.Filtered and combined with the first filtrate,After the combination, the filtrate was filtered again.The filtrate was concentrated under reduced pressure to give a pale yellow oil.The crude product yield is calculated quantitatively.Directly invest in the next reaction (Example 5). |
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With magnesium 2-methylpropan-2-olate; In N,N-dimethyl-formamide; at 60 - 80℃;Industrial scale; |
4,5 kg of N,N-dimethylformamide,<strong>[14047-28-0](R)-9-(2-hydroxypropyl)adenine</strong> (TN01) 20kg was sequentially added to a 200L glass-lined reaction tank.Add 19.4 kg of magnesium tert-butoxide with stirring, and add the stirring.Heating to 60 to 80 C,Slowly add 40kg of diethyl p-toluenesulfonyloxymethylphosphonate,The mixture was stirred for 2 to 4 hours, and sampled by HPLC.The temperature was lowered to 30 to 50 C, 14.9 kg of acetic acid was added, and concentrated under reduced pressure until no significant distillation occurred.Cool down to 25 ~ 35 C, add 200kg of dichloromethane,Transfer to a 300L glass-lined reaction tank by stirring and diluting.Add 18 kg of saturated sodium chloride solution, stir for 3 h, cool to 0 C and stir for 2 h.After suction filtration, the filter cake was rinsed with 50 kg of dichloromethane.Add 50 kg of anhydrous sodium sulfate,Stir well and dry for more than 12h.The mixture was suction filtered, and the filtrate was concentrated under reduced pressure to dryness.24 kg of acetonitrile was added, stirring was started, and concentrated under reduced pressure until no significant fraction was obtained to obtain TN02. The HPLC purity was 85.5%. |
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With magnesium 2-methylpropan-2-olate; In 1-methyl-pyrrolidin-2-one; at 60℃; for 0.75h; |
Step A)The (R)-9-(2-hydroxypropyl) adenine is placed in a mixing kettle,And adding N-methylpyrrolidone for constant stirring, while stirring,Join along the edge of the mixing kettleMagnesium tert-butoxide,Then heat up to 60 C,And joinP-toluenesulfonyloxymethyl phosphate,Maintain the temperature and continue to stir for 45 minutes.Then naturally cool to room temperature and add acetic acid.Adjust the pH in the mixing kettle to 6.5, stir for 25 min, then add ethyl acetate and continue to stir.The solid cake is precipitated and no longer increases, and then centrifuged to obtain a first filter cake and a first filtrate, respectively.Methylene chloride is added to the first filter cake for beating and centrifuging to obtain a second filtrate.The first filtrate and the second filtrate are mixed and stirred, and then concentrated to add cyclohexane.Finally concentrated to give (R)-9 (2-phosphonomethoxypropyl) adenine di(ethyl) ester solution,Standby; where step B)Medium (R)-9-(2-hydroxypropyl) adenine,The mass ratio of magnesium tert-butoxide to diethyl p-toluenesulfonyloxymethyl phosphate is 2:3:4 |
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0.5 mol of R-9-(2-hydroxypropyl)adenine and 400 ml of anhydrous DMF were added to the reaction flask.The reaction liquid was controlled at a temperature of 70 C, 0.475 mol of magnesium t-butoxide was added, and the mixture was stirred for 0.5 hour.0.725 mol of p-toluenesulfonyloxyphosphate diethyl ester was added dropwise; the addition was completed.After stirring at 70 C for 9 hours,The purity of the product in the reaction solution was 92.3% by HPLC.The purity of the raw material R-9-(2-hydroxypropyl)adenine is ?1.0%, the reaction is completed, and the temperature is lowered to 40 C.Anhydrous acetic acid was added dropwise to adjust the pH to 7, and after the addition was completed, the mixture was stirred at room temperature for 30 minutes;The temperature is controlled within 100 C, and DMF is distilled off under reduced pressure.After the completion of the distillation, it was not necessary to isolate the target intermediate to give R-9-[2-(diethylphosphorylmethoxy)propyl] adenine oil.The prepared R-9-[2-(diethylphosphorylmethoxy)propyl]adenine oil was added with 7.5 mol of 48% hydrobromic acid, the temperature was controlled within 100 C, and the reaction was carried out for 15 hours under reduced pressure. , HPLC detection,The purity of the monoester is ?1.0%. After the reaction is completed, 400 g of drinking water is added, and the temperature is lowered to 5-10 C. A large amount of solid is precipitated, suction filtered, and rinsed with a small amount of drinking water to obtain a by-product magnesium p-toluenesulfonate. The filtrate was added to 200 ml of dichloromethane to extract, layered, and the aqueous layer was taken. The pH of the solution was adjusted to 2.7-3.2 with 20% sodium hydroxide solution. A large amount of white solid was precipitated, stirred at room temperature for half an hour, and then cooled to 0-5. After crystallization at C for 5 hours, suction filtration gave a white solid. The solid was recrystallized from 1500 ml of water at 110 C, and dried by filtration to obtain (R)-9-(2-methoxymethoxypropyl)adenine (tenofovir), yield 84.6%, high performance liquid chromatography The peak area of the highest peak is 99.38%. |
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