(αR)-6-Amino-α-methyl-9H-purine-9-ethanol

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To the reaction flask was added 200 ml of N, N-dimethylformamide (DMF)N2 protection, Adenine (30.0 g, 0.222 mol, 1 eq.) Was added, Stirring, NaOH (0.45 g, 0.011 mol) and was addedPropylene carbonate (28.5 g, 0.279 mol, 1.26 eq.), And the temperature was raised to 130 to 140 ° C.12 hours after the sampling test, When the adenine content in 1percent or less, The reaction can be stopped.The temperature slowly reduced to 90 below, 200 ml of toluene, Continue to cool to 0 ~ 5 , And the mixture was stirred for 2 hours.Filtered and dried to give 38.13 g of a white solid, Yield 87percentTo the reaction flask was added 200 ml of N, N-dimethylformamide (DMF), protected with N2, added adenine (30.0 g, 0.222 mol, 1eq .), stirred, NaOH (0 · 45 g, mol) and R-propylene carbonate (28.5 g, 0. 279 mol, 1.3 eq.) and heated to 130 to 140 ° C. 12 hours after the sampling test, when the adenine content of 1percent or less, can stop the reaction. The temperature slowly drops below 90 ° C, add 200 ml of toluene, continue to cool to 0 ~ 5 ° C and stir for 2 hours. Filtered and dried to give 38.13 g of a white solid, 87percent yield, A solution of adenine (3.85g, 28.49 mmol) , (R) - propylene carbonate (2.7 mL, 31.34 mmol), and pulverized sodium hydroxide (60 mg, 1.42 mmol) in anhydrous DMF (80 mL) was heated at 140The Buchi reactor (10 L) was preheated to 150 °C and traces of moisture were blown away with the nitrogen stream. The reactor was filled with argon and cooled down to ~ 70 °C, dry DMF (4 L, ~ 20 ppm of HThe Buchi reactor (10 L) was preheated to 150 °C and traces of moisture were blown away with the nitrogen stream. The reactor was filled with argon and cooled down to ~ 70 °C, dry DMF (4 L, ~ 20 ppm of H40 g (0.296 mol) of adenine To 200 ml of dimethylformamide (DMF)And dissolved 0.94 g (0.0235 mol, 0.08 equiv.) Of sodium hydroxide (NaOH)Followed by stirring at room temperature for 20 minutes39.2 g (0.390 mol, 1.32 Equiv.) Of (R) -propylene carbonate ((R) -propylene carbonate) was added and stirred for 30 minutes.The reaction temperature was 120 [And heated and condensed for 24 hours.Thereafter, the reaction was checked by TLC and HPLC. After the reaction was almost completed (90percent or more), the reaction temperature was cooled to 70 ° C and 240 ml of isopropyl alcohol (IPA) was added to crystallize. Thereafter, the solution was continuously stirred and cooled. The crystals were filtered at 10 ° C, washed with IPA, and dried in a vacuum dryer at 70 ° C to obtain 41 g of HPA (yield: 71.8percent).40 g (0.296 mol) of 6 adenine was dissolved in 200 ml of 7 dimethylformamide (DMF), and 0.94 (0.0235 mol, 0.08 eq.) of 8 sodium hydroxide (NaOH) was added. After 20-min agitation at the room temperature, 39.2 g (0.390 mol, 1.32 eq.) of 9 (R)-propylene carbonate was added and the resultant solution was stirred for 30 minutes. The reaction temperature was elevated to 120° C., and a thermal condensation reaction was activated for 24 hours. Subsequently, the reaction status was examined through TLC and HPLC. After the completion of the reaction (90percent or above), the reaction temperature was reduced to 70° C. and 240 ml of isopropyl alcohol (IPA) was added to active crystallization. Under continuous agitation and cooling, crystals were collected through filtration at 10° C., washed with IPA and then dried out at 70° C. in a low-pressure dryer to obtain 41 g of 5 HPA (yield 71.8percent).(Stage 1 using KOH)Adenine 4 (40 g, 296 mmol, 1.0 eq) and potassium hydroxide (1.66 g, 29.6 mmol, 0.1 eq) were mixed with DMF (190 ml) at 25-30 °C and the mixture was stirred for 10 mm at 25-30 °C. (R)-propylene carbonate 5 (33.6 ml, 39.9 g, 391 mmol, 1.32 eq) was added drop-wise to the reaction mass over10-15 mm at 25-30 °C. The mixture was heated to 120 °C and held at that temperature for 48 h. A clear solution resulted, and the reaction mixture was cooled to 70 °C. A mixture of methanol (120 ml) and iso-propanol (120 ml) was added drop-wise to the reaction mixture over 10 mm, during which time the reaction mixture was allowed to cool to 55 °C, and precipitation of produt was observed. The reaction mixturewas cooled to 5 °C and held at this temperature for I h. The product was isolated by filtration and the cake was washed with a chilled mixture of methanol (10 ml) and isopropanol (10 ml). The resulting solid was dried under vacuum at 70-75 °C, affording HPA 6 as an off-white solid (37 g, 65percent).5.5 1.2 kg of compound XIII was added to a 50 L pressurized reactor, followed by 6.0 L of 1, 4-dioxane and 6.0 L of aqueous ammonia. The temperature was raised to 100 to 110 ° C, and the reflux reaction was sealed for 6 to 8 hours.After the reaction is completed, the heating is turned off. It was concentrated to dryness under reduced pressure at 60 ° C, and was added once with 3.0 L of isopropyl alcohol. The crude product was concentrated to dryness, and 3.0 L of ethanol was added and beaten for 30 minutes.Filtration and drying of the filter cake gave 1.05 kg of compound XIV as a yellow solid product with a purity of 95.2percent and a yield of 96.3percent.0 ° C, A solution of 0.5 mmol of 6-chloro-9- (acetone) purine was addedWas added to 50 ml of the newly prepared aqueous solution of methylamine, 60 ° C for 48 hours, Column chromatography separation, (R) - (+) - 9- (2-hydroxypropyl) adenine, Yield 76percent.8.7 g (50 mmol) of 9-propenyladenine and(S) - (-) - 2, 2'-bis(Diphenylphosphino) -1, 1'-binaphthyl3.1 g (5 mmol)Was added to a reaction flask equipped with methylene chloride, Keep the temperature at 15 ° C, Turn on stirring, then add dropwiseTetramethylpiperidine nitroxideDichloromethane in methylene chloride(Containing tetramethylpiperidine nitrogen oxide 9.4g), dropping completed, Continue to maintain the temperature for 5 hours, the reaction solution was washed with water, Washed with saturated sodium bicarbonate three times, the organic phase was separated, dried over anhydrous sodium sulfate, Concentration under reduced pressure, n-hexane / dichloromethane (10: 1 by volume)Recrystallization Tenofovir intermediates(R) -9- (2-hydroxypropyl) adenine9.1g, Yield 94.7percent, ee value 99.35percent.Addition of adenine (200.00 g), sodium carbonate (7.80 g) and DMF (100 ml) was carried out in a dry three-necked flask at room temperature (R) -propylene oxide (150.50 g) was slowly added, followed by reaction at 95 ° C for 6 h. The reaction was cooled to room temperature and toluene (2000 ml) was slowly added. After the addition, the mixture was stirred at 0 ° C Filtered and the filter cake was washed with n-hexane and dried in vacuo to afford 197.20g (69percent yield) (2R)-1-(6-amino-9H-purin-9-yl)propan-2-ol (II)Example: 6 Preparation of 9-[2-(R)-(Hydroxy)propyl]adenine (I) Method-A Sodium hydroxide (3 g) was added to a stirred suspension of adenine (10 g) in water (50 ml) at room temperature, and the reaction mixture was heated to 100-1 10°C. After 5 hrs at this temperature, the reaction mixture was allowed to cool down to 25°C. Ammonium chloride (3.96 g) and 2-(R)- (+) propylene oxide (6.44 g) were added in succession to the reaction mixture at this temperature. The reaction mixture was maintained at this temperature until the reaction was complete as indicated by TLC. The reaction mixture was concentrated under reduced pressure at 55°C to furnish the desired product, contaminated with unidentified polar impurities. The crude material was purified by column chromatography using a solvent system comprising of methanol and dichloromethane (1 : 9) as the eluant to furnish 9-[2-(R)- (hydroxyl)propyl]adenine as a white solid; yield: 5.5 g.Step 1: The crude R-9- (2-hydroxypropyl) adenine was obtained100 g of adenine (0.74 mol) and 2.35 g (0.058 mol) of sodium hydroxide were added to 500 mlAnd stirred at room temperature for 20 minutes. 96.5 g (0.946 mol) of R-propylene carbonate was added and the temperature was raised to 120-130 ° C to maintain the temperature of the reaction mixtureShould be 16h;After the completion of the reaction by HPLC, the solution of R-9- (2-hydroxypropyl) adenine which had been reacted was distilled off under reduced pressure for 70 ~80percent of the DMF solvent, adding 300ml toluene, stirring evenly, 0 degrees heat 2h, filtration, drying, in the R-9- (2-hydroxypropyl)The crude product of adenine was 136 g, the crude yield was 95.7percent, the purity was 90.8percent, and the isomer was 8.0percent.Step two: packed column, pretreatmentA 150 g of PRP-6A resin was weighed, poured into a glass column, rinsed three times with ethanol, and the column was compactedNo bubbles, the resin height of 28cm, the cylinder uniform, and then rinse with ethyl acetate 3 times, and finally replaced with ethanol, ethyl acetateTo the test without ethyl acetate so far, the column installed backup.Step 3: LoadingThe crude R-9- (2-hydroxypropyl) adenine 6g dissolved in a small amount of water 20ml, into the PRP-6A resin chromatography column, To the sample solution completely adsorbed to the resin column for the sample is completed.Step 4: Elution80percent ethanol as the eluant, pour into the resin column, with air pump pressure elution, flow controlAt 15 ml / min, the eluent was received in 100 ml portions of the receiver bottle, and the content of the product in each bottle was detected by HPLC.Step 5: ConcentrationThe R-9- (2-hydroxypropyl) adenine and the isomer were collected together under vacuum conditions with a purity of more than 99percentConcentrated to dry, distilled ethanol water recovery applied to get more than 99percent purity of R-9- (2-hydroxypropyl) adenine white crystalline powderAnd 4.7 g of isomer having a purity of more than 99percent, and the chromatographic separation yield was 92.9percent of the product and 97.9percent of the isomer.Step 6: Wash the columnRinse the column with 90percent ethanol in water until no liquid is detected. This indicates that the PRP-6A resin column has been flushedClean, you can continue to use the next time.Step 6: Repeat steps 3 through 6 to cycle through the column 6 timesThe results are shown in Table 1 below:Note: In Table 1 above, the chromatographic separation results were obtained in the longitudinal direction for six times. The yield was chromatographic yield, HPLC area integral purity.1) A mixture of 68 g of hydroxypropyl adenine (HPA), 230 g of HDDSPTs, 30 g of magnesium tert-butoxide, and 500 ml of N, N-dimethylformamide was stirred at 80 C for 6 hours, and then reduced. Pressure concentration to remove volatiles;2) Add 500 ml of ethyl acetate, stir and disperse uniformly at room temperature, add 500 ml of 3N hydrochloric acid, and continue stirring for 30 minutes;3) Separate the layers. After the aqueous layer is extracted with 200 ml of ethyl acetate, the pH is adjusted to 3 with 35% sodium hydroxide. The aqueous phase is extracted with dichloromethane (500 ml x 2); the dichloromethane is evaporated under reduced pressure. , Add 500 ml of methanol and 30 ml of dichloromethane to the residue;4) After stirring and heating to dissolve, slowly reduce the temperature to 0 to 5 C, and continue to stir at this temperature for 1 hour;5) Filtration. The filter cake was rinsed with acetone and dried at 50 C to obtain 193 g of tenofovir lipid monoester (HDDSP-TFV) as a white solid.1) Put 68gHydroxypropyl adenine (HPA), 220 g of HDEEPTs, A mixture of 30 g of magnesium tert-butoxide and 500 ml of N, N-dimethylformamide was stirred at 80 C for 6 hours, and then concentrated under reduced pressure to remove volatiles;2) Add 500 ml of ethyl acetate, stir and disperse uniformly at room temperature, add 500 ml of 3N hydrochloric acid, and continue stirring for 30 minutes;3) Separate the layers. After extracting the aqueous layer with 200 ml of ethyl acetate, adjust the pH to 3 with 35% sodium hydroxide; extract the aqueous phase with dichloromethane (500 ml x 2); evaporate the dichloromethane under reduced pressure. , Add 500 ml of methanol and 30 ml of dichloromethane to the residue;4) After stirring and heating to dissolve, slowly reduce the temperature to 0 to 5 C, and continue to stir at this temperature for 1 hour;5) Filtration. The filter cake was rinsed with acetone and dried at 50 C to obtain 188 g of tenofovir lipid monoester (HDEE-TFV) as a white solid.Under nitrogen protection, 1.25 kg of compound XIV, 6.0 kg of DMF and 0.73 kg of magnesium isopropoxide.The temperature was raised to 65 C, and the reaction was stirred for 1 hour.The temperature was lowered to 45-55 C, and DEMP (Formula VI) was slowly added dropwise to the reactor in batches.After the addition was completed, the mixture was stirred at 45 to 55 C for 10 hours.The reaction was determined to be complete by HPLC, and DMF and isopropanol were concentrated under reduced pressure.6.25 kg of concentrated hydrochloric acid was added to the concentrate, the temperature was raised to 90 C, and the reaction was stirred for 10 hours.After the reaction was completed, the temperature was lowered to 10-15 C and stirred for 20-30 minutes.After filtration, the filter cake was washed with 1.0 kg of a dilute hydrochloric acid solution, and the filter cake was discarded.The filtrate was transferred to a reaction kettle, 2.0 kg of dichloromethane was added, and stirred for 15 minutes.Let stand for 30 minutes.The layers were separated, the aqueous phase was collected, and the hydrochloric acid was concentrated under reduced pressure.7.5 kg of water was added to the concentrate, the temperature was raised to 40 C, and the mixture was stirred until dissolved.Slowly add 40% NaOH aqueous solution to adjust the pH to 3.0.After the dropwise addition was completed, the mixture was stirred at 50 C for 3 hours.Cool naturally to room temperature and stir for 10-12 hours.Filter, filter cake was washed with 0.8kg of water, Get tenofovir crude.Purity 96.7%, containing 0.78% condensation impurities, genotoxic impurities 160ppm, The S-isomer impurity was 0.58%, and the isomer was 1.83%.Preparation method of tenofovir alafenamide: phenoxy N- (1-isopropoxyformyl) ethyl phosphoramidite (271.25 g, 1.00 mol), paraformaldehyde (36.80 g, 1.20 mol ) And anisole (0.80 L) were placed in a three-necked flask, and pyridine (39.55 g, 0.50 mol) was slowly added dropwise at 25 C. After the dropwise addition, the temperature was raised to 90 C and stirred for 2 h. The reaction solution was clear and slowly warmed to The reaction was refluxed for 3 h. Cooling, washing with water, drying, The product 3: 2- (2, 3, 4, 5-tetrafluorophenyl) formyl-3- (1-hydroxy-1-phenylmethyl) aminoacrylate in anisole was obtained.Put product 3The anisole solution was cooled to 5 C, Slowly add pyridine (39.55 g, 0.50 mol), After the dropwise addition is completed, continue to drop slowly at this temperature.Benzenesulfonyl chloride (176.65 g, 1.00 mol), After the addition is complete, slowly warm to room temperature and stir for 2 h.Washed with water and dried to obtain product 4:Anisole solution of benzenesulfonyloxymethylphenoxy N- (1-isopropoxyformyl) ethyl phosphonamide.Transfer the anisole solution of product 4 to a three-necked flask and add potassium hydroxide (112.00 g, 2.00 mol)And (R) -1- (6-amino-9H-purin-9-yl) propyl-2-ol (193.21 g, 1.00 mol), Stir at 25 C until the reaction is complete. Water washing, Drying and recovering anisole, After the crude product is resolved, the target product is obtained:Tenofovir alafenamide (144.39 g, total yield 30.30%).Preparation method of tenofovir alafenamide: phenoxy N- (1-isopropoxyformyl) ethyl phosphoramidite (271.25 g, 1.00 mol), paraformaldehyde (36.80 g, 1.20 mol ) And 1, 2-dichloroethane (0.80 L) were placed in a three-necked flask, and N, N-dimethylaniline (60.59 g, 0.50 mol) was slowly added dropwise at 25 C, and the temperature was raised to 90 after the dropwise addition was completed. After stirring at for 2 h, the reaction solution was clear and slowly heated to reflux for 3 h.Cool, wash with water, and dry to obtain product 3:A solution of ethyl 2- (2, 3, 4, 5-tetrafluorophenyl) formyl-3- (1-hydroxy-1-phenylmethyl) aminoacrylate in 1, 2-dichloroethane.The 1, 2-dichloroethane solution of product 3 was cooled to 5 C, and N, N-dimethylaniline (60.59 g, 0.50 mol) was slowly added dropwise. After the dropwise addition was continued, the dropwise addition was continued at this temperatureMethanesulfonic anhydride (174.20 g, 1.00 mol). After the dropwise addition was completed, slowly warm to room temperature and stir for 2 h. Washed with water and dried to obtain product 4:A solution of methanesulfonyloxymethylphenoxy N- (1-isopropoxyformyl) ethyl phosphonamide in 1, 2-dichloroethane.Transfer the 1, 2-dichloroethane solution of product 4 into a three-necked flask, and add potassium bicarbonate (200.00 g, 2.00 mol) and (R) -1- (6-amino-9H-purine-9-yl) Propyl-2-ol (193.21 g, 1.00 mol) was stirred at 25 C until the reaction was complete. It was washed with water, dried, and recovered 1, 2-dichloroethane. The target product was obtained after resolution of the crude product: tenofovir alafenamide (136.33 g, total yield 28.61%).Preparation method of tenofovir alafenamide: phenoxy N- (1-isopropoxyformyl) ethyl phosphoramidite (271.25 g, 1.00 mol), paraformaldehyde (36.80 g, 1.20 mol ) And toluene (0.80 L) were placed in a three-necked flask, and triethylamine (50.50 g, 0.50 mol) was slowly added dropwise at 25 C. After the addition was completed, the temperature was raised to 90 C and stirred for 2 h. The reaction solution was clear and slowly warmed to The reaction was refluxed for 3 h. Cool, wash with water, and dry to obtain product 3:2- (2, 3, 4, 5-tetrafluorophenyl) formyl-3- (1-hydroxy-1-phenylmethyl)Ethyl acrylateOf toluene solution.The toluene solution of product 3 was cooled to 5 C, and triethylamine (50.50 g, 0.50 mol) was slowly added dropwise. After the dropwise addition was continued, the dropwise addition was continued at this temperature.P-toluenesulfonyl chloride(190.65 g, 1.00 mol), slowly warm to room temperature after the dropwise addition, Stir for 2 h.Washed with water and dried to obtain product 4:P-toluenesulfonyloxymethylphenoxy N- (1-isopropoxyformyl) ethyl phosphonamideOf toluene solution.Transfer the toluene solution of product 4 to a three-necked flask, Add potassium carbonate (276.00 g, 2.00 mol) and (R) -1- (6-amino-9H-purin-9-yl) propyl-2-ol (193.21 g, 1.00 mol), and stir at 25 C until The reaction is complete.It was washed with water, dried, and toluene was recovered. The target product was obtained after resolution of the crude product: tenofovir alafenamide (141.10 g, total yield 29.61%).S1. Using (R) -9- (2-hydroxypropyl) adenine as a starting material, After condensation, hydrolysis and esterification reaction with p-toluenesulfonyloxymethyl dipyrfuryl phosphate under magnesium t-butoxideThe reaction temperature is 40-50 C, and free tenofovir disoproxil is obtained;S1. Using (R) -9- (2-hydroxypropyl) adenine as a starting material, condensing, hydrolyzing, and esterifying with p-toluenesulfonyloxymethyl dipyrfuryl phosphate under magnesium t-butoxide catalysis After the reaction, The reaction temperature is 40-50 C, and free tenofovir disoproxil is obtained;Under nitrogen protection, 5.79 g (30.0 mmol) was added to the 100 mL reaction flask.R-9-(2-hydroxypropyl) adenine, 5.61g (33.0mmol)Magnesium tert-butoxide and 50 mL DMF, Warming up to 65 C, Stir for 20 minutes, 14.17 g (30.0 mmol) was added dropwise to the reaction solution.a mixed solution of p-toluenesulfonyloxymethylmethylene diphosphonic acid tetraethyl ester with 15 mL of DMF, After 30 minutes or so, continue to react for 12 hours.DMF was distilled off under reduced pressure, and after cooling to room temperature, 60 mL of 48% HBr solution was slowly added dropwise.The temperature was lowered to 0 C, and solids were precipitated at this temperature for about 12 hours. After suction filtration, the acid solution was filtered off and transferred to a 250 mL round bottom flask, and 50 mL of 48% HBr solution was added thereto, and the reaction was carried out at 95 C for 4 hours under normal pressure.Then use a pump to hydrolyze under low vacuum for 12 hours.Distillation under high vacuum for 2 hours until the liquid is substantially evaporated.Add 100 mL of purified water, stir to dissolve, and extract twice with 25 mL of dichloromethane.The aqueous layer was combined, and the pH was adjusted to about 2.8 with ammonia water. A solid precipitated, suction filtered, washed with water, and dried to give a white solid (the impurity of tenofovir) 5.04 g.

Molecular Weight:193.21
XLogP3:-0.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:193.09635999
Monoisotopic Mass:193.09635999
Topological Polar Surface Area:89.8
Heavy Atom Count:14
Complexity:202
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes