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[ CAS No. 201341-05-1 ] {[proInfo.proName]}

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Chemical Structure| 201341-05-1
Chemical Structure| 201341-05-1
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Product Details of [ 201341-05-1 ]

CAS No. :201341-05-1 MDL No. :MFCD00952920
Formula : C19H30N5O10P Boiling Point : -
Linear Structure Formula :- InChI Key :JFVZFKDSXNQEJW-CQSZACIVSA-N
M.W : 519.44 Pubchem ID :5481350
Synonyms :
Bis(POC)-PMPA;GS 4331

Calculated chemistry of [ 201341-05-1 ]

Physicochemical Properties

Num. heavy atoms : 35
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.63
Num. rotatable bonds : 17
Num. H-bond acceptors : 13.0
Num. H-bond donors : 1.0
Molar Refractivity : 120.92
TPSA : 195.25 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -8.3 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.17
Log Po/w (XLOGP3) : 1.65
Log Po/w (WLOGP) : 3.04
Log Po/w (MLOGP) : -1.09
Log Po/w (SILICOS-IT) : -0.71
Consensus Log Po/w : 1.41

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 3.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -3.17
Solubility : 0.353 mg/ml ; 0.000679 mol/l
Class : Soluble
Log S (Ali) : -5.36
Solubility : 0.00225 mg/ml ; 0.00000433 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -2.58
Solubility : 1.36 mg/ml ; 0.00262 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 3.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.98

Safety of [ 201341-05-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 201341-05-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 201341-05-1 ]

[ 201341-05-1 ] Synthesis Path-Downstream   1~33

  • 1
  • [ 110-17-8 ]
  • tenofovir disoproxil [ No CAS ]
  • [ 202138-50-9 ]
YieldReaction ConditionsOperation in experiment
94.4% In isopropyl alcohol; at 50 - 55℃; 7.2 g (0.149 mol) of tenofovir disoproxil obtained in the step (2) is added to 1000 ml of isopropanol, and the temperature is raised to 50 to 55 C to dissolve.2.43 g (0.209 mol) of fumaric acid was added while hot.Cool down to -5~5 C, stir and crystallize for 2h, filter, dry,89.2 g of tenofovir fumarate was obtained, the yield was 94.4%, and the purity was ?99.5%.The total yield was 80.62%
92.2% In isopropyl alcohol; at 50 - 55℃; for 1h; To 14.9 g (0.0287 mol) of powdered tenofovir dipivoxil was added 149 ml of isopropanol,After the mixture was completely clear, the organic filter was added, and 3.31 g (0.0285 mol) of fumaric acid was added to the filtrate,To 50-55 & lt; 0 & gt; C and stirred at this temperature for 1 h. After completion of the reaction, slowly cool to 0-5 C and at this temperatureContinue for 2h. The dinofloxacin fumarate wet product was obtained by filtration and the wet product was vacuum dried at 30 CThe yield of the product was 16.8 g, the yield was 92.2% and the purity was 99.91%.
90% In methanol; water; at 0 - 75℃; for 0.5h; The compound of Formula 2 (30 g) prepared in Reference Example 2 was dissolved in methanol (50 ml), purified water (150 ml) was added, and the mixture was cooled to 0 to 5 .Fumaric acid (7 g) is added to the other reaction part, methanol (20 ml) is added, purified water (150 ml) is added and the temperature is raised to 70 to 75 C to dissolve.The fumaric acid solution is added dropwise over 30 minutes to the mixed solution of the formula (2) cooled to 0 to 5 so that the temperature does not exceed 25 .After cooling naturally to 20 C to 30 C, crystallization is carried out for 4 hours.Filtered, washed with purified water (20 ml) and then dried under nitrogen for 2 hours to obtain an off-white colored tepofovir disoproxylfumarate salt (33 g).Purity: 99.96%
90% In isopropyl alcohol; at 5 - 50℃; for 3h; 70 ml of isopropyl alcohol and 3.2 g of fumaric acid were added to the oil-like residue, and the temperature was raised to about 50 C to dissolve completely. The reaction solution was slowly cooled to 5 C and stirred for 3 hours. The resulting crystals were filtered and washed with 20 mL of isopropyl alcohol. The obtained solid was vacuum-dried at 40 to obtain 9.4 g (yield: 53%) of crude terpovirdisopropyl fumarate (TDF). 80 ml of isopropyl alcohol was poured into 9.4 g of the above-mentioned tenofovir disoproxyl fumarate (TDF), and the temperature was raised to about 50 C to dissolve completely. The reaction solution was slowly cooled to 5 C and stirred at 5 C for 3 hours. The resulting crystals were filtered, washed with 100 mL of isopropyl alcohol, and vacuum-dried at 40 C to give tenofovir disoproxyl fumarate (TDF) 8.6 g (yield 90%) was obtained.
88% In isopropyl alcohol; at 0 - 50℃; 20 g of tenofovir disoproxil and 4.5 g of fumaric acid were charged into a container, After adding a solvent of 160 ml of isopropyl alcoholThe temperature was raised to about 50 DEG C and stirred for 30 to 60 minutes to completely dissolve.The dissolved reaction solution was cooled to about 25 After cooling slowly, the mixture was cooled to 0 to 5 C and stirred for 2 to 3 hours.The resulting crystals were filtered, washed with 60 ml of isopropyl alcohol, and dried under a humid atmosphere at about 40 C to obtain 21.5 g (yield: 88%) of the title compound.
83% In isopropyl alcohol; at 10 - 50℃; for 4h; The above Step into a salt to concentrate the raffinate 200ml of isopropanol was added, with stirring and heated to 50 C, the reaction flask until clear solution was added 15g of fumaric acid, the addition was complete the reaction was cooled to l C incubation crystallization stirred 4 hours, filtered, and the filter cake was washed with a small amount of isopropyl alcohol after 40 C and dried under vacuum to dryness 69g tenofovir disoproxil fumarate finished. 83% overall yield, 99.4% purity.
83% In isopropyl alcohol; at 10 - 50℃; for 4h; The upward step in the concentrated residual liquid by adding 200 ml of isopropanol, heating under stirring to 50 C, after in the bottle dissolves clear to be reaction, adding 15g fumaric acid, the reaction for cooling to 10 C preserving heat and stirring crystallization 4 hours, filter, with a small amount of isopropanol washing after the 40 C vacuum drying to doing 69g fumaric acid for Fuwei ester finished product. The overall yield is 83%, purity 99.4%.
83% In isopropyl alcohol; at 10℃; for 4h; Add 200ml isopropanol to the concentrated solution and warm to 50 C with stirring. After dissolving in the reaction flask, add15g fumaric acid, add the finished solution cooled to 10 C insulation and stirring crystallization for 4 hours, filter, filter cake with a small amount of isopropyl alcohol washingAnd dried in vacuum at 40 C to obtain 69 g of tenofovir dipivoxil fumarate. The overall yield was 83% and the purity was 99.4%.
83% In isopropyl alcohol; at 10℃; for 4h; To the concentrated solution was added 200 ml of isopropanol,Heated to 50 C with stirring,After being dissolved in the reaction flask,15 g of fumaric acid,After the addition of the reaction solution was cooled to 10 C for 4 hours,The filter cake was washed with a small amount of isopropanol and dried in vacuo at 40 C to obtain 69 g of tenofovir dipivoxil fumarate. The overall yield was 83% and the purity was 99.4%.
83% In isopropyl alcohol; at 10℃; for 4h; Add 200ml of isopropanol to the residue, and heat to 50 C with stirring. After dissolving in the reaction flask, add 15g of fumaric acid. After cooling, the reaction solution is cooled to 10 C and stirred for 4 hours. , Filter cake with a small amount of isopropyl alcohol washed by vacuum drying at 40 to get 69g fumarate tenofovir dipivoxil finished. The overall yield was 83% and the purity was 99.4%.
83% In isopropyl alcohol; at 50℃; for 4h; Add 200ml isopropanol to the concentrated solution and warm to 50 C with stirring. After dissolving in the reaction flask, add15g fumaric acid, add the finished solution cooled to 10 C insulation and stirring crystallization for 4 hours, filter, filter cake with a small amount of isopropyl alcohol washingAnd dried in vacuum at 40 C to obtain 69 g of tenofovir dipivoxil fumarate. The overall yield was 83% and the purity was 99.4%.
83% In isopropyl alcohol; at 10 - 50℃; for 4h;Large scale; Step up concentrated residue was added 200ml of isopropanol was stirred and heated to 50 , the reaction flask until clear solution was added 15g of fumaric acid, completion of the addition the reaction was cooled to 10 insulation mixing crystallization 4 hours, filtered and the cake was washed with a small amount of isopropyl alcohol after 40 vacuum dried affording 69g tenofovir disoproxil fumarate finished.83% overall yield, 99.4% purity.
69% In isopropyl alcohol; at 60℃; for 2.5h; The resulting intermediate (V) (5. 54 g) and fumaric acid (1. 43 g) were dissolved in isopropanol (34 ml) and heated to 60 C for 2.5 h. After cooling to 0 C for 2 h , Filtered, washed with isopropanol, and dried in vacuo to give 4.69 g of 69% yield of tenofovir dipivoxyl fumarate (VI).
45.8% In isopropyl alcohol; at 5 - 60℃;Industrial scale; Intake 75.6 kg of isopropanol,Turn on the stirring and add 4.3kg of fumaric acid.Warm up to 40 ~ 60 C,A solution of the intermediate TN04 obtained in the step 3 of isopropanol (29.3 kg) was further drawn into the fumaric acid system.Add the heating and stirring for 0.5~1h, and reduce the internal temperature to 5~15C.Stirring for 3 to 8 hours,The crude product of tenofovir disoproxil fumarate can be obtained by diafiltration.40 kg of methyl tert-butyl ether and 15 kg of ethyl acetate were added to a 300 L reaction tank, and stirring was started.The crude tenofovir disoproxil fumarate was added, stirred at 10 to 30 C for 2 to 4 hours, and filtered.Wash the filter cake with 50-80 kg of methyl tert-butyl ether.Tenofovir disoproxil fumarate refined product can be obtained by drying under reduced pressure.HPLC purity is 99.2%,The yield was 45.8%; after testing, the chirality of the product reached 100%.More importantly, genotoxic impurities were not detected in isopropyl tosylate,The HPLC spectrum is shown in Figure 1.The retention time is 23.180 min and the relative proportion of the peak area is 100%.
In isopropyl alcohol; at 0 - 45℃; for 2.33333h; Tenofovir disoproxil (2.5 gm) is dissolved in isopropyl alcohol (12.5 ml), fumaric acid (0.6 gm) is added at 25 - 300C and then the temperature is raised to 450C, maintained for 20 minutes. The reaction mass is cooled to 25 - 3O0C and stirred for 1 hour at the same temperature and again mass is. cooled to 0 - 50C, stirred for 1 hour at 0 - 50C. Filtered the material, washed with isopropyl alcohol EPO <DP n="11"/>(2 ml) and finally washed with hexane to give 2.4 gm of tenofovir disoproxil fumarate (HPLC Purity: 99.8%).
In isopropyl alcohol; at 25 - 55℃;Industry scale; Example 2; Tenofovir disoproxil (25 kg) was dissolved in isopropyl alcohol (100 litres) at 25-30 0C. Fumaric acid (10 kg) was added and the mixture was heated to 50-55 C for 1 hour, gradually cooled to 25-30 0C, further chilled to 10C and stirred for 4 hours. The resulting solid was filtered and washed with chilled isopropyl alcohol. The wet cake was stirred in isopropyl acetate (200 Itrs.) at 10-15C for 4 hours. The solid was filtered and washed with chilled isopropyl acetate and dried under vacuum to obtain 30 kg of tenofovir disoproxil fumarate.
In isopropyl alcohol; at 25 - 45℃; for 0.333333h; Tenofovir disoproxil (2.5 gm) is dissolved in isopropyl alcohol (12.5 ml), fumaric acid (0.6 gm) is added at 25-30 C. and then the temperature is raised to 45 C., maintained for 20 minutes. The reaction mass is cooled to 25-30 C. and stirred for 1 hour at the same temperature and again mass is cooled to 0-5 C., stirred for 1 hour at 0-5 C. Filtered the material, washed with isopropyl alcohol (2 ml) and finally washed with hexane to give 2.4 gm of tenofovir disoproxil fumarate (HPLC Purity: 99.8%).
To a clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20C to 35C. Heated to 80C to 85C and stirred for 2 hours and simultaneously removed water liberated. After complete removal of water from the reaction, the solvent was removed completely from the reaction mixture by distillation under vacuum at below 65C and to the obtained residue, charged N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) at 25C to 30C. Heated to 50C to 55C and added chloromethyl isopropyl carbonate (125 gms) at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20C to 25C and washed with cyclohexane (200 ml) and separated the product containing organic layer. To the organic layer charged methylene chloride (500 ml) and stirred for 1 hour at 10C to 15C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50C to 55C and stirred for 20 minutes and added above obtained oily product solution at 50C to 55C. Stirred for 30 minutes at this temperature and cooled to 25C to 30C and stirred for 1 hour. Again cooled to 0C to 5C and stirred for 4 hours. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound as crude (80 gms). In another clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10C to 15C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35C to 40C for 6 hours under reduced pressure to provide the title compound. Yield: 55 gms. HPLC purity: 98.9% HPA: Not detected The XRPD is set forth in Figure-2 The DSC is set forth in Figure-3 Residual Solvents:
EXAMPLE 3 :Preparation of tenofovir disoproxil fumarate.To a clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (20 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20C to 35C. Heated to 80C to 85C and stirred for 2 hours and simultaneously removed water liberated. After complete removal of water from the reaction, the solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 C and to the obtained residue, charged N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) at 25C to 30C. Heated to 50C to 55C and added chloromethyl isopropyl carbonate (125 gms) at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20C to 25C and washed with cyclohexane (2 x 200 ml) and separated the product containing organic layer. To the organic layer charged methylene chloride (500 ml) and stirred for 1 hour at 10C to 15C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50C to 55C and stirred for 20 minutes and added above obtained oily product solution at 50C to 55C. Stirred for 30 minutes at this temperature and cooled to 25C to 30C and stirred for 1 hour. Again cooled to 0C to 5C and stirred for 4 hours. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound as crude (80 gms).In another clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10C to 15C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35C to 40C for 6 hours under reduced pressure to provide the title compound.Yield: 50 gms.[0083] HPLC purity: 98.9%[0084] HP A: Not detected[0085] The XRPD is set forth in Figure-2[0086] The DSC is set forth in Figure-3
55 g In isopropyl alcohol; at 50 - 55℃; for 0.833333h; To a clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20C to 35C. Heated to 80C to 85C and stirred for 2 hours and simultaneously removed water liberated. The solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 C and to the obtained residue N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) were charged at 25C to 30C. Heated to 50C to 55C and chloromethyl isopropyl carbonate (125 gms) was added at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20C to 25C and washed with cyclohexane (200 ml). Methylene chloride (500 ml) was charged into the organic layer and stirred for 1 hour at 10C to 15C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50C to 55C and stirred for 20 minutes and above obtained oily product solution was added at 50C to 55C. Stirred for 30 minutes at this temperature and cooled to 0C to 5C. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound as crude (80 gms). In another clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10C to 15C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35C to 40C for 6 hours under reduced pressure to provide the title compound. Yield: 55 gms. HPLC purity: 98.9%.
In a clean another 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50 C. to 55 C. and stirred for 20 minutes and added above obtained oily product solution at 50 C. to 55 C. Stirred for 30 minutes at this temperature and cooled to 25 C. to 30 C. and stirred for 1 hour. Again cooled to 0 C. to 5 C. and stirred for 4 hours. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35 C. to 40 C. under reduced pressure to provide the title compound as crude (80 gms). [0127] In another clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10 C. to 15 C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35 C. to 40 C. for 6 hours under reduced pressure to provide the title compound. [0128] Yield: 55 gms. [0129] HPLC purity: 98.9%. [0130] HPA: Not detected. [0131] The XRPD is set forth in FIG. 2. [0132] The DSC is set forth in FIG. 3.
In cyclohexane; at 60℃; for 0.166667h; Method B: Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in cyclohexane (3.75 mL), stoichiometric equivalent of fumaric acid was added and mixture was heated to 60C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of cyclohexane and the suspension was filtrated and washed using 5 mL of cyclohexane. The product was obtained in 73 % yield and purity >95 %. The subsequent washing leads to purity improvement but decrease of yield.
In isopropyl alcohol; at 10 - 50℃; for 4h; Step up concentrated residue was added 200ml of isopropanol was stirred and heated to 50 , the reaction flask until clear solution was added 15g of fumaric acid, completion of the addition the reaction was cooled to 10 insulation mixing crystallization 4 hours, filtered and the cake was washed with a small amount of isopropyl alcohol after 40 vacuum dried affording 69g tenofovir disoproxil fumarate finished.83% overall yield, 99.4% purity.
69 g In isopropyl alcohol; at 10 - 50℃; for 4h; Add 200ml of isopropanol to the residue, and heat to 50 C with stirring. After dissolving in the reaction flask, add 15g of fumaric acid. After cooling, the reaction solution is cooled to 10 C and stirred for 4 hours. , The filter cake was washed with a small amount of isopropyl alcohol and dried at 40 C under vacuum to obtain 69 gTenofovir fumarateFinished products. The overall yield was 83% and the purity was 99.4%.
In isopropyl alcohol; at 10℃; for 12h; The tenofovir dipivofuran oil was added with an appropriate amount of isopropyl alcohol and 105 g of fumaric acid,And the mixture was cooled to 10 C. After 12 hours of crystallization,Filtration, filter cake with the right amount of isopropyl alcohol washing, in fumarate tenofovir topiramate furosemide solid. The filter cake was dried at 50 C under reduced pressure to give tenofovir fumarate.
8.073 kg In isopropyl alcohol; at 50 - 55℃; for 2h;Large scale; tenofovir diproxil was transferred to the reactor with 47 kg of isopropanol, Stirring to solution clarification, adding fumaric acid 4.735kg, heating to 50 ~ 55 reaction 2 hours;2) to stop heating, cooling to 30 C, the ice bath cooling to 5 ~ 10 crystallization 1 hour after the centrifugal filter1500r / min; that is, fenvalerate fenvalifol dipivoxil crude product 10.27kg.Finally, the purified fenofloxate fumarate is composed of the following steps:1) isopropyl alcohol recrystallization: the preparation of the obtained solution of tenofovir dipivoxil fumarate into the reactor, addInto 51.35L isopropyl alcohol, stirring heated to 50 ~ 55 , until the reaction solution is dissolved after stirring for 30 minutes, stop heating, cooling toRoom temperature, for use with ice water bath cooling to 5 ~ 10 , keep the temperature stirring crystallization 1 hour, centrifugal rejection filter obtained fumarate fumarateEneveritrile ester isopropyl alcohol recrystallization product 8.54kg.
3.45 kg In isopropyl alcohol; at 50℃;Large scale; 4. 10 L of TNF-3 and isopropyl alcohol were added to a three-necked flask, Stir for 5 minutes, Adding fumaric acid 1.1 kg, Heated to 50 C, The solution was turbid state, Stir the reaction for 2-3 hours. Stop heating, Slowly cooling, Cooling to about 20 when, There will be white solid precipitation, Cooled to 5 C, Slowly stir the crystal overnight. Filter, 40-45 C in vacuo to give a white solid 3.45 kg.
In isopropyl alcohol; at 50℃;Large scale; After the crude tenofovir disoproxil is refined, it is sent to the reaction kettle.Add 20 L of isopropanol, heat to 50 C, and add 1.87 kg of fumaric acid with mechanical stirring.After the fumaric acid is dissolved, the stirring is continued, and the purified tenofovir disoproxil is added, and after completely clarifying,Decrease to room temperature, slowly cool down to 5 C, stir and crystallize for 2 hours; centrifuge to dry,Denotefovir dipivoxil boutique wet product; blast drying,The tenofovir disoproxil fumarate extract is obtained.

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  • 2
  • [ 35180-01-9 ]
  • [ 147127-20-6 ]
  • tenofovir disoproxil [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.5% With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; Tenofovir (60 g, 0.209 mol) was placed in a 500 ml four-necked flask.250 g of N-methylpyrrolidone, and triethylamine (62.3 g, 0.617 mol) was added with stirring.Additional tetrabutylammonium bromide (40.25 g, 0.125 mol) was added.Warming up to 50 C,At this temperature, <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (63.5 g, 0.418 mol) was added dropwise.Investment,Keep warm for 5 to 10 hours,After the end of the heat preservation, after extracting twice with n-heptane 250 ml×2, the water was separated into 480 g of purified water, and extracted three times with isopropyl acetate 240 g+120 g+120 g, and the isopropyl acetate solution was combined and washed twice with an aqueous solution of 180 g×2. , concentrated to dryness under reduced pressure at 40 C, 60 g of isopropanol, 40 CConcentrated to dryness under reduced pressure, adding 100 g of isopropanol, heating and dissolving, cooling to -10 to -20 C, adding 0.5 g of seed crystals, keeping for 2-8 hours, suction filtration,The wet product was dried at 40 C under reduced pressure to obtain tenofovir (99.28 g).Yield 91.5%The purity is 98.3%.
90.6% With triethylamine; N-butylpyridinium tetrafluoroborate; at 40℃; for 1.5h; Tenofovir 28.7 g (0.1 mol), acid-binding agent50.6 g (triethylamine, 0.5 ml),Chloromethyl isopropyl carbonate45.8 g (0.3 mol) and ionic liquid(1-butylpyridinium tetrafluoroborate) was added to the reaction flask and the temperature was raised to 40 (: Stirred for 1.5 hours, after the reaction was completed, cooled to room temperature, the reaction solution was poured into water, extracted with ethyl acetate,The organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure,Concentration of petroleum ether to give Tenofovir disoproxil 47. lg,Yield 90.6%, Book 1 (: 99.47% purity.
87.6% To the reaction flask was added 10 g (0.0348 mol) of anhydrous tenofovir,Tetrabutylammonium bromide (8.5 g, 0.0263 mol)20 ml of N-methylpyrrolidone (NMP) and 9.4 g (0.093 mol) of triethylamine,The temperature was raised to 50 C and stirred at this temperature for 0.5 h.To the reaction solution was slowly added dropwise 22.7 g (0.149 mol) of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong>, and after completion of the dropwise addition,The temperature was raised to 60 C and stirred at this temperature for 4 h. After the reaction is complete,The reaction solution was poured into a cooled aqueous solution of supersaturated sodium chloride and stirred at -10 C for 24 hours. Filter,Washed with cold water, and the resulting solid was dried at 25 C using a blast oven,Get 15.7g crude tenofovir dipinate. The crude product was added to 75 ml of isopropyl ether, heated to reflux temperature, refluxed for 1 h,Then slowly down to 10 , stirring 1h, continue to cool to 0-5 , stirring 2h. Filtered, washed with 28 ml of isopropyl ether at 0-5 C,And dried to obtain 14.9 g of powdered tenofovir dipivoxil, the yield was 87.6% and the purity was 99.1%.
82% A method for synthesizing tenofovir disoproxil, in a dry and clean 1000 mL three-neck reaction flask with mechanical stirring, after nitrogen substitution, 500 mL of N, N-dimethylacetamide was added at room temperature, and tenofovir (PMPA ) 86.1g (0.3 mol, 1.0 equiv), triethylamine 60.6g (0.6 mol, 2.0 equiv), tetrabutylammonium bromide 9.7g (0.03 mol, 0.1 equiv), urea 18.2g (0.3 mol, 1.0 equiv) After stirring for 30min, the temperature was raised to 50 ~ 60 C, and 137.2g (0.9mol, 3 equiv) of POC was slowly added dropwise. After the dropwise addition was completed, the reaction was continued for about 3 hours. After the temperature was lowered, the reaction solution was flushed into 2000mL of ice brine, and stirred Hours, filtered to obtain crude tenofovir dipyrfurate, then beaten once with 300 ml of isopropyl acetate, filtered, and dried to obtain 127.8 g of tenofovir dipyrfurate, purity 98.5%, yield 82.0%.
66% Tenofovir (25 g) and cyclohexane (100 ml) were stirred at 25 C to 30 C.Triethylamine (25 g) was added slowly and the reaction mixture was stirred at 70 C to 75 C for 2 hours.The reaction was completely concentrated at 40 C to 40 C and 1-methyl 2-pyrrolidone (100 ml) was stirred at 25 C to 30 C.Triethylamine (25 ml) was added slowly and the reaction mixture was heated to 50 & lt; 0 & gt; C to 55 [deg.] C for 30 minutes.Chloromethylisopropyl carbonate (65 g) was slowly added to the reaction mixture over about 15-20 minutes.Thereafter, the reaction mixture was stirred at 50 C to 55 C for 4 hours, and then cooled to 25 C to 30 C.Purified water (200 ml) was added and stirred for 30 minutes.Ethyl acetate (200 ml) was added and stirred for 30 minutes, followed by layer separation.Purified water (200 ml) was added to the obtained ethyl acetate layer and stirred for 30 minutes, followed by layer separation.Purified water (200 ml) was added to the obtained ethyl acetate layer and stirred for 30 minutes, followed by layer separation.Magnesium sulfide (50 g) was added to the obtained ethyl acetate layer and stirred for 30 minutes.After filtration, the ethyl acetate layer was completely concentrated at 25 C to 30 C to obtain the compound of formula (2) in an oil phase.Ethyl acetate (100 ml) was added to the resulting oily phase mixture and crystallized at 0 to 5 for 5 hours.Filtered and then dried under nitrogen for 2 hours to obtain 28 g of clear white colored tenofovir disoproxil (Formula 2).(Purity 98.7%)
65.12% With 1-methyl-pyrrolidin-2-one; triethylamine; In cyclohexane; at 50℃; for 16h; Preparation of tenofovir disoproxil: PMPA (25 g), dryN-methyl-2-pyrrolidone (NMP, 6.0 equiv, 50 mL) and cyclohexane(120 mL) were charged to a reactor vessel and agitatedwith a magnetic stirrer (500 rpm) at 50 C. PMPA was driedin advance at about 80 C under vacuum for 24 h. Cyclohexanewas removed in advance by distillation twice under reducedpressure at 50 C. When the reaction was cooled to 45 C,triethylamine (35.2 g, 4.0 equiv) and PEG-600 (31.3 g, 0.6equiv, water content < 1 %) were added. Precipitation oftriethylamine salts of PMPA was caused. The reaction mixturewas heated to 50 C and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong>(66.4 g, 5.0 equiv) was added at this temperature. The reactionwas monitored for completion at 16 h and the initially thicksuspension was almost clear. The reaction samples wereanalyzed by HPLC (purity 88.7 %) which was performed on aliquid chromatograph (Shimadzu, Japan, 10 Atvp) withShimadzu DAD detectoran and ACQUITY BEH C18 column(2.1 mm × 150 mm, 1.7 um). The binary mobile phase wascomposed of water and methanol in proportion 40/60 (v/v).The flow rate was 0.6 mL/min.
Ca. 10% With triethylamine; In N,N-dimethyl-formamide; at 50℃; for 20h; To a stirred suspension of PMPA (7.26 g, 0.026 mmol) in DMF (100 mL) was added Et 3 N (10.8 mL, 0.0778 mmol) at 50 C. The reaction mixture became homogeneous and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (12.1 g, 0.0778 mmol) was added to the reaction mixture and stirring was continued at 50 C. (oil bath temperature) for 20 h. The solvent was removed under reduced pressure and the crude product was chromatographed on a silica gel column. Elution with 10% isopropanol in CH 2 Cl 2 removed all nonpolar impurities. Further elution with the same solvent mixture yielded 1.3 g (about 10%) of the prodrug.
Example 1; <n="13"/>Tenofovir (25 kg) and 1 -methyl 2-pyrrolidinone (100 kg) were stirred at 25-30 C. Triethyl amine (25 kg) was added slowly and the reaction mass was heated to 50-550C for 30 minutes. Chloromethyl isopropyl carbonate (65 kg) was added to the reaction mass gradually over about 15 to 20 minutes. The reaction mass was then heated to 65-700C and stirred for 4 hours and then cooled to 25-30 0C.In another reaction vessel, a saturated solution containing 300 kg sodium chloride, 200 kg of water and 300 kg crushed ice was stirred to a temperature below -15C.The reaction mass from the first step was quenched into the chilled saturated solution maintaining temperature below 0 0C and stirred for 12-15 hours. The resulting solid was filtered and washed with chilled water and spin dried for 1 hour. The solid was further dried in vacuum to obtain 25-30 kg of tenofovir disoproxil Form C.
To a clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20C to 35C. Heated to 80C to 85C and stirred for 2 hours and simultaneously removed water liberated. After complete removal of water from the reaction, the solvent was removed completely from the reaction mixture by distillation under vacuum at below 65C and to the obtained residue, charged N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) at 25C to 30C. Heated to 50C to 55C and added <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (125 gms) at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20C to 25C and washed with cyclohexane (200 ml) and separated the product containing organic layer. To the organic layer charged methylene chloride (500 ml) and stirred for 1 hour at 10C to 15C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50C to 55C and stirred for 20 minutes and added above obtained oily product solution at 50C to 55C. Stirred for 30 minutes at this temperature and cooled to 25C to 30C and stirred for 1 hour. Again cooled to 0C to 5C and stirred for 4 hours. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound as crude (80 gms). In another clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10C to 15C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35C to 40C for 6 hours under reduced pressure to provide the title compound. Yield: 55 gms. HPLC purity: 98.9% HPA: Not detected The XRPD is set forth in Figure-2 The DSC is set forth in Figure-3 Residual Solvents:
With triethylamine;tetrabutylammomium bromide; In 1-methyl-pyrrolidin-2-one; at 50 - 60℃; EXAMPLE 3Preparation of Tenofovir Disoproxil(R)-9-[2-(phosphonomethoxy)propyl]adenine (25 gm), triethyl amine (25 ml) and cyclohexane (200 ml) were combined and heated to remove water and the solvent was distilled off under vacuum. The reaction mass was cooled to room temperature N-methyl pyrrolidinone (55 ml), triethyl amine (25 ml) and tetra butyl ammonium bromide(54 gms) were added to the reaction mixture. The reaction mass was heated to 50-60 C. and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (65 gm) was added and maintained for 4-8 hrs at 50-60 C. and then cooled to 0 C. The reaction mass was diluted with chilled water or ice and precipitated solid product was filtered. The mother liquor was extracted with methylene chloride (150 ml). The methylene chloride layer was washed with water (200 ml). The filtered solid and the methylene chloride layer were combined and washed with water and the solvent was distilled under vacuum. Ethyl acetate was charged to the precipitated solid. The reaction mass was then cooled to 0-5 C. and maintained for 6 hrs. The solid was filtered and dried to produce Tenofovir disoproxil (45 gm).
To a clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20C to 35C. Heated to 80C to 85C and stirred for 2 hours and simultaneously removed water liberated. The solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 C and to the obtained residue N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) were charged at 25C to 30C. Heated to 50C to 55C and <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (125 gms) was added at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20C to 25C and washed with cyclohexane (200 ml). Methylene chloride (500 ml) was charged into the organic layer and stirred for 1 hour at 10C to 15C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50C to 55C and stirred for 20 minutes and above obtained oily product solution was added at 50C to 55C. Stirred for 30 minutes at this temperature and cooled to 0C to 5C. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35C to 40C under reduced pressure to provide the title compound as crude (80 gms). In another clean 3 -necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10C to 15C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35C to 40C for 6 hours under reduced pressure to provide the title compound. Yield: 55 gms. HPLC purity: 98.9%.
To a clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (50 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20 C. to 35 C. Heated to 80 C. to 85 C. and stirred for 2 hours and simultaneously removed water liberated. After complete removal of water from the reaction, the solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 C. and to the obtained residue, charged N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) at 25 C. to 30 C. Heated to 50 C. to 55 C. and added <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (125 gms) at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20 C. to 25 C. and washed with cyclohexane (200 ml) and separated the product containing organic layer. To the organic layer charged methylene chloride (500 ml) and stirred for 1 hour at 10 C. to 15 C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35 C. to obtain oily product and then the oily product was diluted with isopropanol (150 ml).
Starting compound 4 (10 g, 34.8 mmol) was dried at 100 C and 0.1 mbar overnight, and cyclohexane (80 mL) was added, followed by azeotropic distillation. The rest of the cyclohexane was removed in vacuo. After cooling the mixture to RT, dry NMP (40 mL) was added and mixture was stirred for 30 min at RT under argon atmosphere. Then Et3N (10.6 g, 14.7 mL, 105 mmol) was added to the reaction mixture and stirring continued at 45 C for 1 h. Subsequently, <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> (CMIC, 26.5 g, 174 mmol) was added and the reaction was stirred at 60 C for 5 h. The reaction was cooled to RT and cyclohexane (80 mL) was added and the mixture stirred for 15 min and then let settle down for 30 min. Organic phase was removed and the same procedure was repeated once more. Then, the reaction mixture was diluted with cold EtOAc (100 mL) and organic phase was washed with chilled water (2 x 50 mL, 5 C). Water phase was washed with cold EtOAc (1 x 50 mL) and combined organic fractions (EtOAc) were washed with chilled brine (10 %, 5 C, 2 x 50 mL) and dried (Na2SO4). Solvents were immediately evaporated in vacuo at 30 C and the product was codistilled with dry toluene (50 mL) to afford 14.48 g (80%, 75% purity according to HPLC) as yellowish oil (crude Tenofovir disoproxil).
With N-ethyl-N,N-diisopropylamine; In diethyl ether; N,N-dimethyl acetamide; at 55℃; for 8h; 1000ml 400ml reaction flask in ether, 50ml dimethylacetamide and 40g tenofovir monohydrate, openStirring, controlling the temperature of dropping 85g at 20 C under N, N- diisopropylethylamine, dropwise 71/92 100g <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was added dropwise to the reaction system was heated to 55 C insulation 8 hours of reaction, the reaction detected monoester is less than 10%, the reaction solution was concentrated under reduced pressure below 40 C until no liquid outflow, the concentrated residue was added 500ml of ethyl acetate, 200ml 6% sodium hydrogen carbonate solution, stirred after separation the organic phases were washed twice with 200ml of water continues purified, the resulting organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, the resultant concentrated residue was used directly in the next reaction.
With triethylamine; In 1-methyl-pyrrolidin-2-one; acetonitrile; at 20 - 50℃; for 8h; In 1000 ml reaction flask by adding 400 ml acetonitrile, 50mlNMP and 40g tynofovir a water composition, stirring is opened, to control the temperature to 20 C dropping under 67g triethylamine, drops to continue dropping 100g chloro methyl isopropyl carbonate, the reaction system after the dipping temperature is increased to 50 C insulation reaction 8 hours, the detection reaction monoester less than 10%, in the reaction liquid 40 C the following concentrate under reduced pressure until there is no liquid can flow out, in the concentrated residual liquid by adding 500 ml ethyl acetate, 200ml6% of sodium bicarbonate solution, stir layered after extraction, the organic phase continue to use 200 ml purified water washing two times, the resulting organic phase after drying by anhydrous sodium sulfate concentrated under reduced pressure to dry, the resulting concentrated residual liquid directly used for the next reaction.
With N,N-dimethyl acetamide; N-ethyl-N,N-diisopropylamine; In ethanol; at -25 - 60℃; for 10h; 400 ml of ethanol, 50 ml of dimethylacetamide and 40 g of tenofovir monohydrate were added to a 1000 ml reaction flask,Stirring, control the temperature of 20 C dropwise add 85g of N, N-diisopropylethylamine, drop finished to continue dropping 100g chloromethyl carbonateThe reaction system was heated to 50 C for 8 hours and the monoester was detected to be less than 10%. The reaction solution was concentrated under 40 C under reduced pressure until no liquid flowed out and concentrated to the residue 500 ml of ethyl acetate, 200 ml of a 6% solution of sodium hydrogencarbonate,After stirring, the layers were extracted and the organic phase was washed twice with 200 ml of purified water,The obtained organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure,The resulting concentrated residue was used directly in the next step.
With 1-methyl-pyrrolidin-2-one; potassium carbonate; In diethyl ether; at 20 - 50℃; for 8h; A 1000 ml reaction flask was charged with 400 ml of ether,50 ml of N-methylpyrrolidone and 40 g of tenofovir monohydrate,Turn on agitation,Control temperature: 91 g of potassium carbonate was added dropwise at 20 C,After dropping, 100 g of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was continuously added dropwise,After the completion of the dropping, the reaction system was heated to 50 C for 8 hours,Detection of the reaction less than 10% monoester,The reaction solution was concentrated under reduced pressure at 40 C or lower until no liquid flowed out,To the concentrated residue was added 500 ml of ethyl acetate,The organic phase was washed twice with 200 ml of purified water. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting concentrated residue was used directly in the next step reaction.
With potassium carbonate; In N,N-dimethyl acetamide; acetonitrile; at 50℃; for 8h; 400 ml of acetonitrile, 50 ml of dimethylacetamide and 40 g of tenofovir monohydrate were added to a 1000 ml reaction flask, and stirring was started. 91 g of potassium carbonate was added dropwise at a controlled temperature of 20 C, and 100 g of chloromethyl carbonate Isopropyl ester. After dropping, the reaction system was heated to 50 C for 8 hours. The monoester was detected to be less than 10%. The reaction solution was concentrated under reduced pressure at 40 C until no liquid flowed out. To the concentrated residue was added 500 ml And the organic phase was washed twice with 200 ml of purified water. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting concentrated residue was directly purified by filtration, washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. For the next reaction.
With triethylamine; In 1-methyl-pyrrolidin-2-one; ethanol; at 20 - 57℃; for 8h; In a 1000 ml reaction flask was added 400 ml of ethanol,50 ml of N-methylpyrrolidone and 40 g of tenofovir monohydrate,Turn on agitation,Control temperature: 67 g of triethylamine was added dropwise at 20 C,After dropping, 100 g of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was continuously added dropwise,After dropping, the reaction system was heated to 57 for 8 hours,Detection of the reaction less than 10% monoester,The reaction solution was concentrated under reduced pressure at 40 C or lower until no liquid flowed out,To the concentrated residue was added 500 ml of ethyl acetate,200 ml of 6% sodium hydrogencarbonate solution,After stirring, the layers were extracted,The organic phase was washed twice with 200 ml of purified water,The obtained organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure,The resulting concentrated residue was used directly in the next step.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20 - 57℃; for 8h; 400 ml of acetonitrile, 50 ml of dimethylformamide and 40 g of tenofovir monohydrate were added to a 1000 ml reaction flask,Stirring, control the temperature of 20 C dropwise add 85g of N, N-diisopropylethylamine, drop finished to continue dropping 100g chloromethyl carbonateIsopropyl ester. After the completion of the reaction, the reaction system was heated to 57 C for 8 hours. The reaction was carried out with the monoester content of less than 10%The liquid was concentrated under reduced pressure at 40 C to no liquid. To the concentrated residue was added 500 ml of ethyl acetate, 200 ml of 6% carbonAnd the organic phase is washed twice with 200 ml of purified water twice, and the obtained organic phase is treated with anhydrous sulfurDried over sodium sulfate, concentrated to dryness under reduced pressure, and the resulting concentrated residue was used directly in the next step
With potassium carbonate; In ethanol; N,N-dimethyl-formamide; at 20 - 57℃; for 8h;Large scale; In 1000 ml reaction flask by adding 400 ml of ethanol, 50 ml dimethyl formamide and 40g tenofovir a water composition, stirring is opened, to control the temperature to 20 C dropping under 91g the potassium carbonate, drops to continue dropping 100g chloro methyl isopropyl carbonate, the reaction system after the dipping temperature is increased to 57 C insulation reaction 8 hours, the detection reaction monoester less than 10%, in the reaction liquid 40 C the following concentrate under reduced pressure until there is no liquid can flow out, in the concentrated residual liquid by adding 500 ml ethyl acetate, 200ml6% of sodium bicarbonate solution, stir layered after extraction, the organic phase continue to use 200 ml purified water washing two times, the resulting organic phase after drying by anhydrous sodium sulfate concentrated under reduced pressure to dry, the resulting concentrated residual liquid directly used for the next reaction.
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 70℃; for 10h; 300 g of N-methylpyrrolidone was added to the reaction vessel,Triethylamine 90 g and tenofovir 25 g,Stirring,Heated to 70 C,40 g of chloromethylisopropylcarbonate was added dropwise,The reaction was stirred for 10 hours with heating and the reaction was stopped. Adding appropriate amount of ethyl acetate, filtering, washing with appropriate amount of ethyl acetate filter residue, washing filtrate, add appropriate amount of water washing 3 times, adding anhydrous sodium sulfate dehydration, filtration. Filtrate by 55 C vacuum distillation, evaporated to dry, tenofovir dipivoxil oil. The molar ratio of tenofovir to triethylamine was 1:10.
With benzyltriethylammonium bromide; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 4h; Intermediate (IV) (3.67g) in dry DMF and a three-necked flask (16ml) and dissolved with stirring at room temperature, followed Triethylamine (7.1ml) and triethyl benzyl ammonium bromide (5.23g), then heated to 60 C, was added chloromethyl isopropyl Carbonate (8.5ml), the same temperature, the reaction 4h, cooled to room temperature water was added (16ml) and ethyl acetate (38ml), mixed well After co-liquid separation, the aqueous phase was extracted with ethyl acetate (2 × 38ml), the combined organic phase was washed with water (2 × 100ml), saturated chloride Sodium washing solution (100ml), Na 2 SO 4 dried, filtered, and the filtrate was concentrated to obtain a solid intermediate (V) 5.54g, crude product 84%, directly into the next step (Example 9).
24.64 kg With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 46 - 55℃; for 4h;Autoclave; Inert atmosphere; Large scale; N-methylpyrrolidone 49.25 kg was added to the reaction kettle, and 10 mg of tenofovir was added to the autoclaveAnd then add 17.2kg of triethylamine and 12kg of tetrabutylammonium bromide to stir well and heat the reaction vessel under nitrogen protection to46 , dropping <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> 30.3kg, control the reaction temperature does not exceed 55 , and continue to stir the reaction to 4 small, The temperature of the reactor to be cooled to 40 C, twice were added 50kg of cyclohexane washing, stirring for 30 minutes, staticSet for 15 minutes, discard the cyclohexane phase, keep the liquid after washing;2) To the washed liquid was added 50 kg of water and 110 kg of ethyl acetate for extraction, delamination, retention of ethyl acetatephase. Two times with 55kg ethyl acetate washing water twice, combined with ethyl acetate phase;3) The organic phase liquid obtained in step 2) was washed with 55 kg of 5% by mass of sodium bicarbonateAnd then with 55kg0.02% by mass of ammonia water washing three times, and finally with 55k saturated sodium chloride for washing aThe washed organic phase liquid was dried over 26.25 kg of anhydrous sodium sulfate for 2 hours to obtain a filtrate by filtration; filtrate 40 ~After distillation, tenofovir dipivoxil 21.64kg.
3.7 kg 3. 8 L NMP into the reaction flask, Adding 2.0 kg of TNF-2, Heated to 45 C, Stir for 30 minutes, The solution was turbid. Adding triethylamine and tetrabutylammonium bromide, Stir for 30 minutes, Heated to 50 C. Pass nitrogen protection, Dropping isopropyl chloromethyl carbonate, 1-2 hours dripping finished, Stirring reaction. 2 hours after every half hour sampling to send liquid phase monitoring, Monitor the content of TNF-3 and monoester (when the product peak is no longer increasing and the impurity peak is increasing, the reaction is stopped). After completion of the reaction, Stop heating, Cooled to room temperature, To the reaction solution was added 3 L of cyclohexane, Stirring at room temperature, Static stratification. NMP followed by addition of cyclohexane 3L, Stir and wash away. NMP phase was added 8 L of water and 8 L of dichloromethane,30 C, Static separation.The aqueous phase was continuously extracted several times with dichloromethane, To almost no product in the water phase. The combined dichloromethane phase, The organic phase was washed with 3L * 6 saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and decolored with activated charcoal. filter, Concentrated under reduced pressure to dry, A yellow oil was obtained as 3.7 kg.
30.0 mL of N-methylpyrrolidone and 11.6 mL of triethylamine were added to 8.0 g of tenofovir (PMPA), and the reaction solution was heated to 60C and stirred for 30 minutes. 20 g of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was added at 60C , stirred at the same temperature for 4 hours, cooled to 5C , and 50 ml of water was slowly added thereto. The mixture was stirred at 15 DEG C for 1 hour, extracted twice with 30 mL of dichloromethane, and the organic layer was separated and washed twice with 20 mL of water. The organic layer was dried over anhydrous magnesium sulfate (5 g) and concentrated under reduced pressure to obtain an oil-form of tenofovir disoproxil.
With dmap; triethylamine; In 1-methyl-pyrrolidin-2-one; at 10 - 50℃; for 3h;Large scale;Catalytic behavior; The temperature was 10 to 20 C, PMPA (287.2 g, 1.0 mol)Triethylamine (303.6 g, 3.0 mol), 4-dimethylaminopyridine (DMAP, 12.2 g, 0.10 mol) was added to a 1.44 kg solution of N-methylpyrrolidone,Chloromethyl isopropyl carbonate (762.3 g, 5.0 mol) was added dropwise at a temperature not exceeding 30 C under stirring,Followed by stirring at 40 to 50 C for 3 hours.After the reaction was reduced to 15 to 25 C, 4.31 kg of ethyl acetate was added and stirred for 0.5 h.The filtrate was added with 4.31 kg of purified water, and the aqueous phase was added twice with 2.15 kg of ethyl acetate.The organic phase was combined and the organic phase was washed successively with 4.31 kg of saturated sodium bicarbonate solution, 4.31 kg of saturated sodium chloride solution, dried over 215 g of anhydrous sodium sulfate, filtered and concentrated to give the product.Yield 90.6% and monoester impurity control was 2.31%.
41.4 g of Tenofovir monohydrate (commercially available or prepared as disclosed in CN1264387A) was added to 164 g of N-methylpyrrolidone at 20~25 C.,Then added under stirring triethylamine 40g, 20 ~ 25 C under stirring for 0.5 hours,Chloromethyl isopropyl carbonate was added 100g, warmed to 55-65 C incubated for 5 hours;Stop heating, cooling to 20 ~ 30 C, adding ethyl acetate 320g, purified water 180g,0 ~ 5 C under stirring after the separation, the lower layer and then 110g of ethyl acetate at 0 ~ 5 C under extraction,Combined ethyl acetate layer, purified water 0 ~ 5 C washed twice, each 320g,30 ~ 35 C concentrated ethyl acetate; cyclohexane was added to the concentrate 150mL,20 ~ 25 C under stirring for 10 hours, filtered, cyclohexane 20mL rinse,Tenofovir disoproxil, white solid.
Tenofovir (PMPA) prepared in Example 1, 100 g and 1-methyl-2-pyrrolidone (420 mL) were stirred at 25 C to 30 C. 2.54 mol equivalent of triethylamine 82.9 g were slowly added, and the reaction mixture was heated at 50 C to 55 C for 30 minutes. 175.0 g of 3.5 molar equivalents of chloromethylisopropyl carbonate (CMIC) was slowly added to the reaction mixture over about 15 to 20minutes. Thereafter, the reaction mixture was stirred at 60 C to 70 C for 3 hours,and it was cooled to 25 to 30 ..1.0 liter of ethyl acetate was added, and the mixture was stirred for 30 minutes and filtered. 1 L of a 20% NaCl aqueous solution was added, followed by stirring, followed by layer separation. 1 L of a 5% aqueous solution of NaHCO3 was added thereto, followed by stirring, followed by layer separation. 50 g of anhydrous sodium sulfate was added to the obtained ethyl acetate layer, followed by stirring for 30 minutes. After filtration, the ethyl acetate layer was completely concentrated at 30 C to 35 C to obtain 167.9g of Tenofovir disoproxil, as an oil phase(Purity 97.1%). 400 mL of the organic solvent shown in Table 3 below was added to the obtained oily phase mixture and crystallization was carried out at 0 C to 5 C for 5 hours. Filtered and dried under reduced pressure to obtain 108 g of Tenofovir disoproxil.
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃;Large scale; After pretreating the crude tenofovir obtained in step S02,And 16L N-methylpyrrolidone, 4.44kg of triethylamine, after stirring evenly,Start to warm to 50 C, stir, add 11.15 kg of isopropyl chloromethyl carbonate,After stirring, the reaction was completely quenched by cooling, and after cooling, 12 L of cyclohexane was added twice.Stir, centrifuge, layer, discard the upper layer of cyclohexane, and transfer the filtrate from the lower layer to the reaction vessel.Add 30 L of water and 20 L of ethyl acetate, stir for 30 minutes, and let stand for stratification.The aqueous layer was extracted once with 10 L of ethyl acetate.Add 1.0 kg of anhydrous sodium sulfate, stir dry, centrifuge,The filtrate is transferred to the transfer reactor in batches, concentrated under reduced pressure, and the concentrate is transferred to the reaction vessel.Tenofovir disoproxil give crude ester.
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; S03 condensation: After pretreating the crude tenofovir obtained in the step S02, and stirring 16 L of N-methylpyrrolidone and 4.44 kg of triethylamine, the temperature is raised to 50 C and stirred.11.15 kg of isopropyl chloromethyl carbonate was added dropwise, stirred, and the reaction was completely cooled and quenched.After cooling, add 12 L of cyclohexane twice, stir, centrifuge, layer, and discard the upper layer of cyclohexane. The lower layer of the filtrate was transferred to a reaction kettle, and 30 L of water and 20 L of ethyl acetate were added.After stirring for 30 minutes, the layers were allowed to stand, and the aqueous layer was extracted with 10 L of ethyl acetate.Wash with 20L of 10wt% brine, add 1.0kg anhydrous sodium sulfate, stir dry, centrifuge,The filtrate is transferred to the transfer reactor in batches, concentrated under reduced pressure, and the concentrate is transferred to the reaction vessel.Denotefovir dipivoxilCrude.
With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 45 - 55℃; for 1h; Under nitrogen protection,Tenofovir 50g (0.174mol),Chloromethyl isopropyl carbonate132.8g (0.87mol),Tetrabutylammonium bromide 56.1g (0.174mol)Into 150 ml of N-methylpyrrolidone,Warming up to 45 C,Control temperature 45~55 C, start adding dropwise 44.0g (0.435mol) of triethylamineThe esterification reaction is carried out, the addition is completed, and the reaction is kept for 1 hour.Cooling to 10~20 C, to obtain an esterification reaction solution;HPLC detection of the esterification reaction solution,
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50 - 70℃;Industrial scale; 60 kg of N-methylpyrrolidone and 12 kg of intermediate TN03 were placed in a 200 L glass-lined reaction tank.Stirring was started and 12 kg of triethylamine was added.The heating temperature was controlled to an internal temperature of 50 to 70 C, and 33 kg of isopropyl chloromethyl carbonate was added.After the addition, the temperature was raised to an internal temperature of 50 to 70 C, and the mixture was stirred for 6 to 10 hours, and sampled by HPLC.After the reaction was completed, the temperature was lowered to 10 to 30 C, and 24 kg of purified water was added.Add 55.3 kg of cyclohexane to a 500 L reaction tank and start stirring.The reaction solution was transferred from a 200 L reaction tank to a 500 L reaction tank.Stir for 15 min, let stand for stratification,The lower layer was collected; 36 kg of n-hexane was added to a 500 L reaction tank.Turn on the agitation,The lower aqueous layer was transferred to a reaction tank and stirred for 15 min, and the layers were allowed to stand, and the lower aqueous layer was collected. Transfer the collected water layer to a 500L reaction tank,Add 30 kg of purified water and add 96 kg of ethyl acetate.Stir for 15 min, let stand for stratification,The upper layer was collected; 30 kg of ethyl acetate was added to a 500 L reaction tank.Turn on the agitation and transfer the lower aqueous layer to the reaction tank.Stir for 15 min, let stand for stratification, collect the upper layer,The ethyl acetate organic layer was combined in a 500 L reaction tank, and the 500 L reaction tank was stirred.Adding an already prepared aqueous solution of sodium chloride to the reaction tank,After stirring for 15 min, the layer was allowed to stand, and the lower aqueous layer was discarded to obtain an ethyl acetate layer.Transfer the ethyl acetate layer to a clean 300L glass-lined reaction tank.It was dried by adding 12 kg of anhydrous sodium sulfate.After suction filtration, the filter cake was rinsed with 9 kg to 27 kg of ethyl acetate.The filtrate was pumped into a reaction tank, and concentrated under reduced pressure until no fraction was obtained to obtain TN04.The HPLC purity was 80.2%.
With tetrabutylammomium bromide; triethylamine; In 1-methyl-pyrrolidin-2-one; at 55℃; for 0.166667h; step C)The prepared tenofovir is placed in a mixing kettle,And join at the same timeIsopropyl chloromethyl carbonate,N-methylpyrrolidone and tetrabutylammonium bromide were stirred for 20 min.Then add triethylamine and warm to 55 C for 10 min.Then, it was naturally cooled to room temperature, and then washed with cyclohexane, and allowed to stand for stratification.And keep the lower layer of the solution, then add water and ethyl acetate.After stirring well, let stand and layer, and keep several layers, then wash with 10% NaClPolyester, adding anhydrous sodium sulfate, drying and filtering to obtain an intermediate product.At this point, the intermediate product was again placed in the mixing kettle, and isopropanol and fumaric acid were added for stirring.Then heated to 55 C, stirred until clear, and then naturally cooled to room temperature,And stirring at the same time, after reaching room temperature, continue to cool to 8 C, at this time to maintain the temperature,Crystallize and centrifuge, and dry the solid in a vacuum.A tenofovir disoproxil product is obtained; wherein the equivalent weight of isopropyl chloromethyl carbonate in step D) is 4 eq.
17.9 g With tetrabutylammomium bromide; triethylamine; In N,N-dimethyl-formamide; at 55 - 65℃; for 8h; In step S1, tenofovir and isopropyl chloromethyl carbonate are prepared.Step S2, adding 15.2 g of tenofovir (0.05 mol), 15.1 g of triethylamine (0.15 mol) and 4.0 g of tetrabutylammonium bromide to 100 mL of N,N-dimethylformamide, stirring and dissolving, heating up To 55 C, 38.1 g of isopropyl chloromethyl carbonate (0.25 mol) was added dropwise, and the first reaction temperature was controlled from 55 C to 65 C for 8 hours.Cool to room temperature, add 100 mL of ethyl acetate and 100 mL of water, stir, and separate.The organic phase was washed twice with 50 mL of saturated sodium chloride, washed and dried over anhydrous sodium sulfate, filtered, and then evaporated.Add 100 mL of methyl tert-butyl ether and stir to clarify.-5 C ~ 0 C rapid stirring for 4 hours into a white turbid liquid,Filtration and drying gave 17.9 g of a white solid.
S1. Esterification reaction: Add 35 kg of tenofovir to the reaction tank and dissolve it in 140 Kg of N-methylpyrrolidone.Add 23.8Kg of molecular sieve and stir for 30 minutes to remove water; then add 35Kg of triethylamine and stir at 30 C for 2 hours to mix well;Then, 91Kg of <strong>[35180-01-9]chloromethyl isopropyl carbonate</strong> was added to carry out the esterification reaction at 30 C, and the reaction was stopped after 25 hours of reaction.The components in the reaction solution were detected by HPLC;S2. Extraction and separation: adding 4.5 times the mass of ethyl acetate equivalent to the reaction system to the reaction system of S1. For extraction,Stir for 30 minutes and filter in a centrifuge. The resulting filtrate is washed with saturated brine and stirred for 20 minutes.The first organic phase and the aqueous phase were separated by standing. The aqueous phase was extracted again with about 4.5 times the mass of ethyl acetate, and the liquid phase was separated to obtain a second organic phase.Combine the first organic phase and the second organic phase, wash them twice with saturated brine, and dry with anhydrous sodium sulfate.Centrifuging to separate anhydrous sodium sulfate from the system to obtain a tenofovir disoproxil solution;

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  • 3
  • [ 922494-97-1 ]
  • [ 201341-05-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (R)-N4-dimethylaminomethylideno-9-(2-phosphonomethoxypropyl)adenine bis(isopropyloxycarbonyloxymethyl) ester With acetic acid In water at 25 - 55℃; for 3h; Stage #2: With triethylamine In water; ethyl acetate 1.III (R)-N4-Dimethy.arninomethyledino-9-(2-phosphonomethoxypropyl) adenine bis(isopropyloxycarbonyloxymethyl) ester (10 gm) is added to 80% acetic acid (80 ml) at 25 - 3O0C, the temperature is raised to 50 - 550C and maintained for 3 hours at the same temperature. Then acetic acid is distilled under vacuum at 7O0C. Water (40 ml) and ethyl acetate (130 ml) are added to the residue, pH of the solution is adjusted to 7.0 with triethylamine and then separateαl the layers. The resulting orgarϖc layer is washed with 10% sodium chloride solution (35 ml) and distilled under a vacuum to give 8 gm of tenofovir disoproxil (HPLC Purity: 99.2%).
Stage #1: (R)-N4-dimethylaminomethylideno-9-(2-phosphonomethoxypropyl)adenine bis(isopropyloxycarbonyloxymethyl) ester With water; acetic acid at 25 - 55℃; for 3h; Stage #2: With triethylamine In water; ethyl acetate 1.III (R)-N4-Dimethylaminomethyledino-9-(2-phosphonomethoxypropyl) adenine bis(isopropyloxycarbonyloxymethyl) ester (10 gm) is added to 80% acetic acid (80 ml) at 25-30° C., the temperature is raised to 50-55° C. and maintained for 3 hours at the same temperature. Then acetic acid is distilled under vacuum at 70° C. Water (40 ml) and ethyl acetate (130 ml) are added to the residue, pH of the solution is adjusted to 7.0 with triethylamine and then separated the layers. The resulting organic layer is washed with 10% sodium chloride solution (35 ml) and distilled under a vacuum to give 8 gm of tenofovir disoproxil (HPLC Purity: 99.2%).
  • 4
  • [ 87-69-4 ]
  • [ 201341-05-1 ]
  • [ 1197785-87-7 ]
YieldReaction ConditionsOperation in experiment
89.8% In methanol; ethanol at 15 - 20℃; 13 Preparation of Tenofovir disoproxil L-tartrate Form A 50.0 g (96.3 mmol) of tenofovir disoproxil and 14.4 g (95.9 mmol) of L-tartaric acid were dissolved in a mixed solvent of 500 mL of methanol / ethanol (3: 2 by volume) , Dissolved completely stirred and cooled to 15 ~ 20 ° C, continue stirring crystallization; suction filtration; cake was dried under reduced pressure at 25 ~ 30 ° C, was obtained tenofovir disoproxil L- tartrate crystal form eight 57.88, yield 89.8%.
In acetonitrile at 5 - 60℃; Crystallization of solid forms at microliter scale.; A small quantity, about 3 mg of the starting material was stock dosed in a each of the wells of a 96-well plate using in 1 ,4-dioxane as stock solvent. The plates were placed under vacuum until the solvent evaporated. Following, the counter ions were added in each well at a counter-ion:free-base ratio of 1.1 :1 , either by solid dosing or by a stock solution in 1 ,4- dioxane or water. In the cases that the counter ion was dosed by means of a stock solution, the solvent was removed by evaporation. Subsequently, 30μl_ of a crystallization solvent was added and the plates were heated to 6O0C for 60 min. The solutions were cooled with 1.1°C/h to a temperature of 5 or 2O0C where they remained for 24h. Subsequently, the solvents were evaporated from the wells under 20 kPa pressure at 20-25 0C for 19-24h. The resulting residue was harvested and analyzed by X-ray powder diffraction.The counter ions used and the corresponding crystallization solvents are listed in Table 1.
  • 5
  • [ 144-62-7 ]
  • [ 201341-05-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
In chloroform at 20 - 60℃; Crystallization of solid forms at microliter scale.; A small quantity, about 3 mg of the starting material was stock dosed in a each of the wells of a 96-well plate using in 1 ,4-dioxane as stock solvent. The plates were placed under vacuum until the solvent evaporated. Following, the counter ions were added in each well at a counter-ion:free-base ratio of 1.1 :1 , either by solid dosing or by a stock solution in 1 ,4- dioxane or water. In the cases that the counter ion was dosed by means of a stock solution, the solvent was removed by evaporation. Subsequently, 30μl_ of a crystallization solvent was added and the plates were heated to 6O0C for 60 min. The solutions were cooled with 1.1°C/h to a temperature of 5 or 2O0C where they remained for 24h. Subsequently, the solvents were evaporated from the wells under 20 kPa pressure at 20-25 0C for 19-24h. The resulting residue was harvested and analyzed by X-ray powder diffraction.The counter ions used and the corresponding crystallization solvents are listed in Table 1.
In toluene at 60℃; for 0.166667h; 13 Example 13: Preparation of Tenofovir disoproxil oxalate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), stoichiometric equivalent of oxalic acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
  • 6
  • [ 110-15-6 ]
  • [ 201341-05-1 ]
  • [ 1637632-97-3 ]
YieldReaction ConditionsOperation in experiment
In methanol; water at 5 - 60℃; Crystallization of solid forms at microliter scale.; A small quantity, about 3 mg of the starting material was stock dosed in a each of the wells of a 96-well plate using in 1 ,4-dioxane as stock solvent. The plates were placed under vacuum until the solvent evaporated. Following, the counter ions were added in each well at a counter-ion:free-base ratio of 1.1 :1 , either by solid dosing or by a stock solution in 1 ,4- dioxane or water. In the cases that the counter ion was dosed by means of a stock solution, the solvent was removed by evaporation. Subsequently, 30μl_ of a crystallization solvent was added and the plates were heated to 6O0C for 60 min. The solutions were cooled with 1.1°C/h to a temperature of 5 or 2O0C where they remained for 24h. Subsequently, the solvents were evaporated from the wells under 20 kPa pressure at 20-25 0C for 19-24h. The resulting residue was harvested and analyzed by X-ray powder diffraction.The counter ions used and the corresponding crystallization solvents are listed in Table 1.
In acetonitrile at 60℃; for 1h; Tenofovir disoproxil succinate (suc2) from free base; About 100 mg of tenofovir disoproxil free base was solid dosed into an 8ml via. together with about 22 78 mg of succinic acid The crystallization solvent (acetonitrile) were added so that the concentration with respect to the free base was 100 mg/ml The vials were heated to 6O0C for 60 min The solutions were cooled with 1 1°C/h to a temperature of 50C where they remained for 24h The solids were obtained by centrifugation with 3000 rpm speed for 10 min and dried under vacuum at 40 0C for about 5 h The solid was labelled Suc2
In toluene at 60℃; for 0.166667h; 11 Example 11 Example 11 Preparation of Tenofovir disoproxil succinate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), stoichiometric equivalent of succinic acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
  • 7
  • [ 69-72-7 ]
  • [ 201341-05-1 ]
  • [ 1161758-49-1 ]
YieldReaction ConditionsOperation in experiment
In water; acetone at 20 - 60℃; Crystallization of solid forms at microliter scale.; A small quantity, about 3 mg of the starting material was stock dosed in a each of the wells of a 96-well plate using in 1 ,4-dioxane as stock solvent. The plates were placed under vacuum until the solvent evaporated. Following, the counter ions were added in each well at a counter-ion:free-base ratio of 1.1 :1 , either by solid dosing or by a stock solution in 1 ,4- dioxane or water. In the cases that the counter ion was dosed by means of a stock solution, the solvent was removed by evaporation. Subsequently, 30μl_ of a crystallization solvent was added and the plates were heated to 6O0C for 60 min. The solutions were cooled with 1.1°C/h to a temperature of 5 or 2O0C where they remained for 24h. Subsequently, the solvents were evaporated from the wells under 20 kPa pressure at 20-25 0C for 19-24h. The resulting residue was harvested and analyzed by X-ray powder diffraction.The counter ions used and the corresponding crystallization solvents are listed in Table 1.
  • 8
  • [ 81-07-2 ]
  • [ 201341-05-1 ]
  • [ 2271279-41-3 ]
YieldReaction ConditionsOperation in experiment
In nitromethane at 5 - 60℃; Crystallization of solid forms at microliter scale.; A small quantity, about 3 mg of the starting material was stock dosed in a each of the wells of a 96-well plate using in 1 ,4-dioxane as stock solvent. The plates were placed under vacuum until the solvent evaporated. Following, the counter ions were added in each well at a counter-ion:free-base ratio of 1.1 :1 , either by solid dosing or by a stock solution in 1 ,4- dioxane or water. In the cases that the counter ion was dosed by means of a stock solution, the solvent was removed by evaporation. Subsequently, 30μl_ of a crystallization solvent was added and the plates were heated to 6O0C for 60 min. The solutions were cooled with 1.1°C/h to a temperature of 5 or 2O0C where they remained for 24h. Subsequently, the solvents were evaporated from the wells under 20 kPa pressure at 20-25 0C for 19-24h. The resulting residue was harvested and analyzed by X-ray powder diffraction.The counter ions used and the corresponding crystallization solvents are listed in Table 1.
2.5 g In ethyl acetate at 20℃; Sonication; 1 Example 1: Preparation of tenofovir disoproxil saccharin 2.08 g of tenofovir disoproxil and 0.73 g of saccharin were added to 20 mL of ethyl acetate, and the solution was sonicated at room temperature to obtain a clear solution, which was filtered into a crystallization vessel, covered with a gas permeable film, and slowly volatilized in a ventilated cabinet at room temperature. When the liquid was evaporated, a clear or off-white solid was obtained; and dried under vacuum at 25 °C for 24 h to give a white powder (2.5 g).
  • 10
  • [ 35180-01-9 ]
  • [ 1215085-37-2 ]
  • [ 201341-05-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (x)C6H15N*C9H14N5O4P With tetrabutylammomium bromide; triethylamine In 1-methyl-pyrrolidin-2-one at 50 - 60℃; Stage #2: chloromethyl isopropyl carbonate In 1-methyl-pyrrolidin-2-one at 0 - 60℃; 3 Example 3 : Preparation of Tenofovir disoproxil(R)-9-[2-(phosphonomethoxy)propyl]adenine (25 gm), triethyl amine (25 ml) and cyclohexane (200 ml) were combined and heated to remove water and the solvent was distilled off under vacuum. The reaction mass was cooled to room temperature N-methyl pyrrolidinone (55 ml), triethyl amine (25 ml) and tetra butyl ammonium bromide(54 gms) were added to the reaction mixture. The reaction mass was heated to 50-60°C and chloromethyl isopropyl carbonate (65 gm) was added and maintained for 4-8 hrs at 50- 60°C and then cooled to 0°C. The reaction mass was diluted with chilled water or ice and precipitated solid product was filtered. The mother liquor was extracted with methylene chloride (150 ml). The methylene chloride layer was washed with water (200 ml). The filtered solid and the methylene chloride layer were combined and washed with water and the solvent was distilled under vacuum. Ethyl acetate was charged to the precipitated solid. The reaction mass was then cooled to 0-5 °C and maintained for 6 hrs. The solid was filtered and dried to produce Tenofovir disoproxil (45 gm).
  • 11
  • [ 180587-75-1 ]
  • [ 201341-05-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: hydrogen bromide / water / 5 h / 90 - 95 °C 1.2: 4 h / 0 - 30 °C / pH 2.5 - 3 2.1: triethylamine / cyclohexane / 2 h / 80 - 85 °C 2.2: 4 h / 50 - 55 °C
Multi-step reaction with 2 steps 1.1: hydrogen bromide / water / 2 h / 90 - 95 °C 1.2: 5 h / 0 - 30 °C / pH 2.5 2.1: triethylamine / cyclohexane / 2 h / 20 - 85 °C 2.2: 4 h / 25 - 55 °C 2.3: pH 6.5 - 7.5
Multi-step reaction with 2 steps 1.1: hydrogenchloride; N,N-dimethyl-formamide / 4 h / 0 - 95 °C 2.1: triethylamine / cyclohexane / 2 h / 20 - 85 °C / Dean-Stark 2.2: 4 h / 25 - 55 °C
Multi-step reaction with 2 steps 1.1: hydrogen bromide / water / 5 h / 25 - 95 °C 2.1: triethylamine / cyclohexane / 2 h / 20 - 85 °C 2.2: 4 h / 25 - 55 °C
Multi-step reaction with 2 steps 1: hydrogen bromide / 10 h / Reflux 2: triethylamine / 1-methyl-pyrrolidin-2-one / 10 h / 70 °C
Multi-step reaction with 2 steps 1: hydrogen bromide / 8 h / 80 °C 2: triethylamine; benzyltriethylammonium bromide / N,N-dimethyl-formamide / 4 h / 60 °C
Multi-step reaction with 2 steps 1.1: trimethylsilyl bromide / 1-methyl-pyrrolidin-2-one / 19 h / 70 °C / Large scale 2.1: triethylamine; tetrabutylammomium bromide / 1-methyl-pyrrolidin-2-one / 45 °C / Large scale 2.2: 0.5 h / 50 °C / Inert atmosphere; Large scale
Multi-step reaction with 2 steps 1.1: trimethylsilyl bromide / acetonitrile / 1 h / 65 °C 2.1: triethylamine / 1-methyl-pyrrolidin-2-one / 0.5 h / 60 °C 2.2: 4 h / 60 °C
Multi-step reaction with 2 steps 1: trimethylsilyl bromide / 1-methyl-pyrrolidin-2-one / 75 °C / Large scale 2: triethylamine / 1-methyl-pyrrolidin-2-one / 50 °C / Large scale
Multi-step reaction with 2 steps 1.1: trimethylsilyl bromide / acetonitrile / 60 - 75 °C / Large scale 1.2: 22 - 50 °C / pH 0.9 - 2.8 / Large scale 2.1: triethylamine / N,N-dimethyl-formamide / 20 h / 50 °C
Multi-step reaction with 2 steps 1: trimethylsilyl bromide / 10 h / 0 - 80 °C / Industrial scale 2: triethylamine / 1-methyl-pyrrolidin-2-one / 50 - 70 °C / Industrial scale
Multi-step reaction with 2 steps 1.1: sodium bromide; chloro-trimethyl-silane / 10 h / 30 - 60 °C / Large scale 1.2: pH 2.5 - 3.5 / Large scale 2.1: triethylamine / 1-methyl-pyrrolidin-2-one; water / 4 h / 40 - 60 °C 2.2: 4 h / 30 - 55 °C

  • 12
  • [ 147127-20-6 ]
  • tenofovir disoproxil [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: tenofovir With triethylamine In cyclohexane at 20 - 85℃; for 2h; Stage #2: With chloromethyl isopropyl carbonate In 1-methyl-pyrrolidin-2-one; cyclohexane at 25 - 55℃; for 4h; Stage #3: With ammonia In water 3 EXAMPLE 3 :Preparation of tenofovir disoproxil fumarate.To a clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket, addition funnel and dean-stark apparatus was charged cyclohexane (400 ml) and tenofovir (20 gms, obtained from example 1) and triethyl amine (34 gms) at temperature 20°C to 35°C. Heated to 80°C to 85°C and stirred for 2 hours and simultaneously removed water liberated. After complete removal of water from the reaction, the solvent was removed completely from the reaction mixture by distillation under vacuum at below 65 °C and to the obtained residue, charged N-methyl pyrrolidinone (150 ml) and triethyl amine (34 gms) at 25°C to 30°C. Heated to 50°C to 55°C and added chloromethyl isopropyl carbonate (125 gms) at same temperature and stirred for 4 hours. After completion of the reaction, the reaction mass was cooled to 20°C to 25°C and washed with cyclohexane (2 x 200 ml) and separated the product containing organic layer. To the organic layer charged methylene chloride (500 ml) and stirred for 1 hour at 10°C to 15°C. Filtered the salts formed and washed the filtrate with water (500 ml), separated the layers and charged water (500 ml) to the organic layer. Adjusted pH to 6.5 to 7.5 with 10% ammonia solution and separated the organic layer from the aqueous layer. The solvent was removed from the organic layer under vacuum at below 35°C to obtain oily product and then the oily product was diluted with isopropanol (150 ml). In a clean another 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged isopropanol (350 ml) and Fumaric acid (19 gms). Heated to 50°C to 55°C and stirred for 20 minutes and added above obtained oily product solution at 50°C to 55°C. Stirred for 30 minutes at this temperature and cooled to 25°C to 30°C and stirred for 1 hour. Again cooled to 0°C to 5°C and stirred for 4 hours. Filtered the product and washed with chilled isopropanol (75 ml). The wet product was dried at 35°C to 40°C under reduced pressure to provide the title compound as crude (80 gms).In another clean 3-necked 1L round bottom flask equipped with a mechanical stirrer, thermometer socket and addition funnel was charged ethyl acetate (450 ml) and crude product (80 gms) at temperature 10°C to 15°C. Stirred the slurry for 1 hour and filtered the product and washed with chilled ethyl acetate (50 ml). The wet product was dried at 35°C to 40°C for 6 hours under reduced pressure to provide the title compound.Yield: 50 gms.[0083] HPLC purity: 98.9%[0084] HP A: Not detected[0085] The XRPD is set forth in Figure-2[0086] The DSC is set forth in Figure-3
  • 13
  • [ 35180-01-9 ]
  • [ 180587-75-1 ]
  • [ 201341-05-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (R)-diethyl (((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate With 1-methyl-pyrrolidin-2-one; chloro-trimethyl-silane; sodium bromide at 60℃; for 12h; Inert atmosphere; Stage #2: chloromethyl isopropyl carbonate With triethylamine at 60℃; for 6h; 4.1.4. General procedure for the synthesis of 9-{2-[O,O′-bis(pivaloyloxymethyl)phosphonomethoxy]ethyl}adenine (11) and (R)-9-{2-[O,O′-bis(isopropoxycarbonyloxymethyl)phosphonomethoxy]propyl}adenine (12) General procedure: A solution of 4 or 5 (1equiv, 10mmol) and sodium bromide (2.1 equiv, 21mmol) in anhydrous N-methylpyrrolidinone (10mL) was stirred vigorously under argon. Trimethylsilyl chloride (4equiv, 40mmol) was added dropwise and the mixture was heated at 60°C for 12h. The reaction was monitored by HPLC until complete dispartition of the starting material (S1). When completion was observed, the reaction mixture was diluted with anhydrous ethyl acetate (16mL) and stirred for 5min. The ethyl acetate and remaining trimethylsilyl chloride were then concentrated in vacuo at 60°C. Anhydrous isopropyl alcohol (1.5mL) was then added to the reaction mixture and stirred for 15min. The mixture was diluted with anhydrous ethyl acetate (16mL) and solvents were evaporated under reduced pressure at 60°C. Chloromethyl pivalate (POMCl, 5equiv, 50mmol) for the synthesis of 11 or chloromethyl isopropylcarbonate 10[50] (POCCl, 5equiv, 50mmol) for the synthesis of 12 and triethylamine (3 equiv, 30mmol) were added to the mixture and the reaction mixture was stirred at 60°C for 6h. The reaction was diluted in anhydrous ethyl acetate (16mL), stirred for 5min, and the ethyl acetate and remaining triethylamine were concentrated in vacuo at 60°C. The reaction mixture was diluted in ethyl acetate (160mL) and extracted with water (60mL), dried over magnesium sulphate, filtered, and concentrated to dryness under reduced pressure. The resulting oil was purified by silica gel flash chromatography [eluent, stepwise gradient of methanol (0-5%) indichloromethane] to afford the desired product as a white powder.
  • 14
  • [ 201341-05-1 ]
  • [ 1173789-34-8 ]
YieldReaction ConditionsOperation in experiment
32% With 2,4-bis(methylthio)-1,3-dithia-2,4-diphosphetane-2,4-disulfide In benzene at 0 - 80℃; for 2.5h; 4.1.5. General procedure for the synthesis of 9-{2-[O,O′-bis(pivaloyloxymethyl)thiophosphonomethoxy]ethyl}adenine (13) (R)-9-{2-[O,O′-bis(isopropoxycarbonyloxymethyl)thiophosphonomethoxy]propyl}adenine (14) General procedure: A solution of 11 or 12 (1equiv, 2.5mmol) and 2,4-Bis(methylthio)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (1equiv, 2.5mmol) in anhydrous benzene (40mL) was stirred at 80°C for 30min. The mixture was then stirred at 0°C for 2h. After filtration through a celite pad, benzene was concentrated in vacuo and the residue purified by silica gel flash chromatography [eluent, stepwise gradient of methanol (0-5%) in dichloromethane] to afford the desired product as a white powder.
  • 15
  • [ 201341-05-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
38% Stage #1: tenofovir disoproxil With water at 60℃; Stage #2: 4.1.6. General procedure for the synthesis of (R)-9-{2-[O-mono(isopropoxycarbonyloxymethyl)phosphonomethoxy]propyl}adenine (15) (R)-9-{2-[O-mono(isopropoxycarbonyloxymethyl)thiophosphonomethoxy]propyl}adenine (16) General procedure: A solution of 12 or 14 (1equiv, 0.05mmol) in water (5mL) was stirred vigorously at 60°C. The reaction was maintained at 60°C and monitored by HPLC-MS for complete conversion to 15 or 16. Typical retention times: tR=0.49min, PMPA, ESI-MS [M+H] m/z=288.0; tR=0.48min, 9, ESI-MS [M+H] m/z=304.10; tR=4.78min, 15, ESI-MS [M+H] m/z=404.09; tR=6.36 and 6.50min (2 diastereoisomers), 16, ESI-MS [M+H] m/z=420.09; tR=8.04min, 12, ESI-MS [M+H] m/z=520.19; tR=8.92min, 14, ESI-MS [M+H] m/z=536.10. When completion was observed, the reaction mixture was extracted with ethyl acetate (5mL) and the aqueous layer concentrated in vacuo and lyophilized. The crude product was purified on reverse phase C18 (biotage SNAP cartridge KP-C18-HS 33g, flow : 10mL/min, UV-detector : 260nm, Eluent A : TEAB 0.05M, eluent B : solution A containing 50% of acetonitrile, gradient starts at 100% eluent A with an increase to 10% eluent B after 66min, to 20% eluent B after 83min and to 100% eluent B after 116min). Each fraction was analysed by HPLC (S1), pure fractions were collected and eluted on a Dowex 50WX2 column (Na+ exchange) to give the pure compound as sodium salt as a white powder after freeze-drying.
  • 16
  • [ 73-24-5 ]
  • [ 201341-05-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide / 16 h / 140 °C 2.1: magnesium 2-methylpropan-2-olate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 2.2: 20 h / 35 °C / Inert atmosphere 3.1: sodium bromide; 1-methyl-pyrrolidin-2-one; chloro-trimethyl-silane / 12 h / 60 °C / Inert atmosphere 3.2: 6 h / 60 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 100 - 120 °C / Inert atmosphere 1.2: 8 h / 120 °C 2.1: magnesium 2-methylpropan-2-olate / N,N-dimethyl-formamide; water / 44 h / -15 - 20 °C / Inert atmosphere 3.1: hydrogenchloride / water / 0.5 h / 140 °C / Microwave irradiation 4.1: triethylamine / 1-methyl-pyrrolidin-2-one / 1 h / 45 °C / Inert atmosphere 4.2: 5 h / 60 °C
Multi-step reaction with 4 steps 1.1: sodium carbonate / N,N-dimethyl-formamide / 6 h / 95 °C 2.1: lithium tert-butoxide / N,N-dimethyl-formamide / 2 h / 0 - 20 °C 2.2: 0 °C 3.1: hydrogen bromide / 8 h / 80 °C 4.1: triethylamine; benzyltriethylammonium bromide / N,N-dimethyl-formamide / 4 h / 60 °C
Multi-step reaction with 4 steps 1: tert.-butyl lithium / N,N-dimethyl-formamide 2: magnesium 2-methylpropan-2-olate / 1-methyl-pyrrolidin-2-one / 0.75 h / 60 °C 3: trimethylsilyl bromide / 0.42 h / 60 °C 4: tetrabutylammomium bromide; triethylamine / 1-methyl-pyrrolidin-2-one / 0.17 h / 55 °C
Multi-step reaction with 4 steps 1.1: sodium hydroxide / N,N-dimethyl-formamide / 145 °C / Large scale 2.1: magnesium 2-methylpropan-2-olate / N,N-dimethyl-formamide / 1 h / 50 °C 2.2: 4 h / 60 °C 3.1: sodium bromide; chloro-trimethyl-silane / 10 h / 30 - 60 °C / Large scale 3.2: pH 2.5 - 3.5 / Large scale 4.1: triethylamine / 1-methyl-pyrrolidin-2-one; water / 4 h / 40 - 60 °C 4.2: 4 h / 30 - 55 °C

  • 17
  • [ 56-84-8 ]
  • [ 201341-05-1 ]
  • [ 1571075-19-8 ]
YieldReaction ConditionsOperation in experiment
In water at 46 - 51℃; for 2h; 1 Preparation of tenofovir disoproxil aspartate Preparation of tenofovir disoproxil aspartate [79] Into a 2,000 reaction vessel, add 50.0 g of tenofovir disoproxil free base, 750 of purified water, and 15.4 g of aspartic acid (L-aspartic acid; Aldrich). Heat to 46-51 and stir for 2 hours. Cool to room temperature and stir for 15 hours. Filter the solution and wash the filtercake with 50 of purified water and dry it for 2 hours at 45 to obtain 50.6 g of the white title compound, tenofovir disoproxil aspartate. [80] [81] HPLC purity : 99.68% [82] 1H NMR (400, D2O): 8.30(s, 1H), 8.18(s, 1H), 5.54-5.42(m, 3H), 5.39-5.34(m, 1H), 4.91-4.83(m, 2H), 4.42-4.38(m, 1H), 4.23-4.18(m, 1H), 4.12-4.06(m, 1H), 3.95-3.92(m, 2H), 3.84-3.78(m, 1H), 2.92-2.86(m, 1H), 2.82-2.75(m, 1H), 1.28-1.24(m, 15H) ppm [83] Melting point : 109
  • 18
  • [ 202138-50-9 ]
  • tenofovir disoproxil [ No CAS ]
YieldReaction ConditionsOperation in experiment
35 g With sodium hydrogencarbonate; In water; ethyl acetate; at 20℃; for 0.666667h;pH 7.0; Preparation of tenofovir disoproxil free base [72] Into a 1,000 reaction unit, add 50.0 g of tenofovir disoproxil fumarate (purity 98.60%, Luna Chemicals, China), 250 of ethyl acetate, and 250 of purified water. Suspend and stir for 10 minutes at room temperature. Add saturated sodium bicarbonate solution dropwise until pH 7.0. Stir for 30 minutes and orient the solution for 10 minutes. Discard the aqueous layer. Dry the organic layer with anhydrous magnesium sulfate. Filter and concentrate. When the volume of the concentrate reaches 125, the solids start to precipitate. Stop the concentration and stir at room temperature for 2 hours. Cool the reactor to 5 and stir for 2 hours. Upon filtering, dry the filtercake for 2 hours at 45 to obtain 35.0 g of the white title compound, tenofovir disoproxil free base. [73] [74] HPLC purity : 99.61% [75] 1H NMR (400, D2O): 8.16(s, 1H), 8.05(s, 1H), 5.52-5.39(m, 3H), 5.33-5.28(m, 1H), 4.89-4.77(m, 2H), 4.34-4.30(m, 1H), 4.16-4.05(m, 2H), 3.93-3.90(m, 1H), 3.80-3.74(m, 1H), 1.27-1.21(m, 15H) ppm [76] Melting point : 101.5
  • 19
  • tenofovir disoproxil [ No CAS ]
  • [ 147127-20-6 ]
YieldReaction ConditionsOperation in experiment
85.4% In ethyl acetate at 0 - 10℃; for 2h; Cooling with ice; 1.2 The esterification reaction solution obtained in the step (1) is slowly added dropwise to a mixture of 90 ml of ethyl acetate and 910 ml of ice water.The crystals were mixed and the addition was completed. The mixture was stirred and crystallized at 0 to 10 ° C for 2 h, filtered, suction filtered, and the filter cake was dried to obtain 77.2 g of tenofovir.The yield is 85.4%, and the purity is ≥97.0%;
  • 20
  • [ 331-39-5 ]
  • [ 201341-05-1 ]
  • [ 1402422-79-0 ]
YieldReaction ConditionsOperation in experiment
0.5 g In water; isopropyl alcohol at -10 - 60℃; for 4.08333h; 11 Example 11 Preparation of Tenofovir Disoproxil Caffeate Form I Charged 1 gm of Tenofovir disoproxil, 0.347 gms of Caffeic acid and 5 ml of IPA into a round bottom flask at 25° to 35° C. Heated the resultant reaction mass to about 55° C. to 60° C. to form a clear solution and then cooled to -5° to -10° C. Added 30 ml of DM water for 5 minutes. The reaction mass was maintained for 2 hrs at -5° to -10° C. and raised temperature to 25° C. to 30° C. and maintained for 2 hours at same temperature. Added 10 ml of DM Water to the precipitated product and maintained for 15 minutes at same temperature. The precipitated solids were filtered and dried at 40° C. to 45° C. for 1 hour to afford 0.5 gms of the title compound. [0168] HPLC Purity: 98.70% [0169] The XRPD is set forth in FIG. 6.
  • 21
  • [ 7400-08-0 ]
  • [ 201341-05-1 ]
  • [ 1402422-81-4 ]
YieldReaction ConditionsOperation in experiment
2.6 g In acetonitrile at -20 - 65℃; for 0.5h; 14 Example 14 Preparation of Tenofovir Disoproxil p-Coumarate Form I Charged 3 gms of Tenofovir disoproxil, 0.948 gms of p-coumaric acid and 15 ml of acetonitrile in a round bottom flask at temperature 25° C. to about 35° C. and heated to 60° C. to 65° C. to form a clear solution. The solution was cooled to -15° C. to -20° C. and stirred for 30 minutes. The precipitated solid was filtered and dried at 40° C. to 45° C. for 2 hrs to afford 2.6 gms of the title compound. [0177] HPLC purity: 99.06% [0178] The XRPD is set forth in FIG. 8.
  • 22
  • [ 530-59-6 ]
  • [ 201341-05-1 ]
  • [ 1402422-82-5 ]
YieldReaction ConditionsOperation in experiment
3.9 g In tetrahydrofuran; di-isopropyl ether at 25 - 65℃; for 3.5h; 15 Example 15 Preparation of Tenofovir Disoproxil Sinapate Form I Charged 3 gms of Tenofovir disoproxil, 1.29 gms of sinapic acid and 15 ml of Tetrahydrofuran at 25° C. to 35° C. in to a round bottom flask and heated to 60° C. to 65° C. to form a clear solution. The resultant solution was cooled to 25° C. to 30° C. and added 75 ml of Isopropyl ether for 30 minutes. The reaction mass was maintained for 3 hrs at 25° C. to 30° C. and precipitated solid was filtered and dried at 40° C. to 45° C. for 1 hour to afford 3.9 gms of the title compound. [0180] HPLC Purity: 98.57%. [0181] The XRPD is set forth in FIG. 9.
  • 23
  • [ 1135-24-6 ]
  • [ 201341-05-1 ]
  • [ 1402422-78-9 ]
YieldReaction ConditionsOperation in experiment
0.5 g In isopropyl alcohol at 25 - 45℃; for 1.5h; 7 Example 7 Preparation of Tenofovir Disoproxil Ferulate Form AL3 Tenofovir Disoproxil (5 gm) and Ferulic acid (2.05 gm) were added to IPA (25 ml) at 25° C. and then heated to 40-45° C. to form a clear solution. Maintained the reaction mass for about 1 hour and then cooled to 25-30° C. and stirred for hour. The obtained solid was filtered and dried at 40° C. for 2 hours to get solid state form of Tenofovir disoproxil ferulate (0.50 gm). [0160] The XRPD is set forth in FIG. 3
  • 24
  • [ 65-86-1 ]
  • tenofovir disoproxil [ No CAS ]
  • 9-[2-[(R)[[bis[[isopropoxycarbonyl]oxy]methoxy]phosphinyl]methoxy]propyl]adenine orotate [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With triethylamine; In water; dimethyl sulfoxide; at 20 - 30℃; 3.0 g of <strong>[65-86-1]orotic acid</strong> was added to the vessel,and after addition of the solvent dimethylsulfoxide 100and stirred for 10 to 20 minutes at about 25 completelydissolved.In the dissolved reaction solution,Put 10 g tenofovir disoproxil ,and completely dissolved by stirring at about 25 for 10 to 20 minutes.The other container wascharged with 100 ml of water and 40 mul of triethylamine, then the reactionmixture was dissolved at about the 20 ~ 30 was added slowly for 10 to 20 minutes.After stirring the mixture for1-2 hours at about 25 , crystals were filtered and Washed with30 ml of water and dried under a warm air at about 40 C to obtain the titlecompound (12.6 g, yield: 97%).
85% In methanol; water; at 20 - 70℃; Example 1>Preparation of tenofovir disoproxil orotate (1)[88][89]Tenofovir disoproxil (25g) was added to a reaction unit and was dissolved with methanol (125ml). Orotic acid (7.96g) and purified water were added to the reaction solution, which was then suspended for 10 minutes at room temperature and heated for an hour at internal temperature of 70 until all of the solid has been dissolved. The reaction solution was reacted at internal temperature of 20 for 1-2 hours to obtain crystals. The obtained crystal was vacuum-filtered and washed with methanol:water (100ml, 1:3) and dried. The dried crystal was vacuum dried at internal temperature of 60 for 15 hours.[90][91]Purity (by HPLC): 99.3%, Yield: 27.69g (85%)[92]1H NMR(DMSO-d6) deltappm 11.29(s,1H,NH), 10.8(s,1H,NH), 8.14(s,1H,CH), 8.04(s,1H,CH), 7.36(s,2H,NH2),5.97(s,1H,CH), 5.48-5.56(m,4H,CH2), 4.79-4.81(m,2H,CH2), 4.14-4.26(ddd,2H,CH2), 3.92-4.01(m,3H,CH), 1.22(s,12H,CH3), 1.04(s,3H,CH3).
  • 25
  • [ 201341-05-1 ]
  • [ 1453166-76-1 ]
YieldReaction ConditionsOperation in experiment
80% With phosphoric acid In isopropyl alcohol at 60℃; for 1.5h; 1 Example 1:Preparation of Tenofovir disoproxil dihydrogenphosphate from Tenofovir disoproxil base [0028] Tenofovir disoproxil base (2.78 g) was dissolved in isopropanol (90 ml) in the 100 ml vessel (Easy Max) at 60°C. Afterwards 1 equivalent of phosphoric acid (0.33 ml 85 %) was added dropwise into the vessel. After 90 min thesuspension was cooled down to 0 °C by the cooling ramp 0.1 K/min. Tenofovir disoproxil phosphate was filtered, washedup two times by isopropanol (2x30 ml) and dried up by room temperature overnight (16 hours). The isolated yield ofcrystallization was 80 % (HPLC: 99.56 %). Chromatographic result can be found in the appendix (Figure 4). Particlesize distribution was obtained by scanning electron microscope. Most of the particles were smaller than 100 mm (Figure 5).
80% With phosphoric acid In isopropyl alcohol at 60℃; for 1.5h; 1 Example 1: Preparation of Tenofovir disoproxil dihydrogenphosphate from Tenofovir disoproxil base Example 1: Preparation of Tenofovir disoproxil dihydrogenphosphate from Tenofovir disoproxil base Tenofovir disoproxil base (2.78 g) was dissolved in isopropanol (90 ml) in the 100 ml vessel (Easy Max) at 60 °C. Afterwards 1 equivalent of phosphoric acid (0.33 ml 85 %) was added dropwise into the vessel. After 90 min the suspension was cooled down to 0 °C by the cooling ramp 0.1 K/min. Tenofovir disoproxil phosphate was filtered, washed up two times by isopropanol (2x30 ml) and dried up by room temperature overnight (16 hours). The isolated yield of crystallization was 80 % (HPLC: 99.56 %). Chromatographic result can be found in the appendix (Figure 4). Particle size distribution was obtained by scanning electron microscope. Most of the particles were smaller than 100 μηη (Figure 5).
With phosphoric acid In toluene at 60℃; for 1h; 7 Example 7: Preparation of Tenofovir disoproxil dihydrogenphosphate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), 1.1 -1.5 stoichiometric equivalent of phosphoric acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
  • 26
  • [ 110-17-8 ]
  • [ 201341-05-1 ]
  • [ 202138-50-9 ]
YieldReaction ConditionsOperation in experiment
In toluene at 60℃; for 0.166667h; 12 Example 12: Preparation of Tenofovir disoproxil hemifumarate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), 0.5 equivalent of fumaric acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
In ethanol at 30 - 40℃; for 2h; 1.S2-1.S3 S2. Weigh 20 kg of free tenofovir dipyrfurate obtained in step S1 and place it in a 200L glass reaction flask, add 60L of absolute ethanol, and raise the temperature to 30-40 ° C.A salt formation reaction was performed. After the reaction solution was clarified, 2.3 kg of fumaric acid was added. After 2 hours of reaction,30L of ethyl acetate was added, and then the temperature was lowered to 0 to 5 ° C, and the mixture was crystallized by stirring for 3 to 4 hours, and filtered by suction to obtain a white powder; S3. Centrifuge the white powder of step S2 for 3 to 4 hours and place it in a 100L double cone vacuum dryer for vacuum drying. The initial drying temperature is 45 ° C and the vacuum degree is ≤-0.08MPa.After that, the temperature rises by 5 ° C every 4h. After drying for 12h,A white solid was obtained, namely amorphous tenofovir disoproxil hemifumarate. The amorphous tenofovir disoproxil hemifumarate prepared by the above method has a purity of 99.32% and a solvent residue of 0.05%.
In ethanol at 30 - 40℃; for 2h; 1.S2-1.S3; 2.S2-2.S3; 3.S2-3.S3; 4.S2-4.S3; 1-3 S2. Weigh 20 kg of free tenofovir dipyrfurate obtained in step S1 and place it in a 200L glass reaction flask, add 60L of absolute ethanol, and raise the temperature to 30-40 ° C.A salt formation reaction was performed. After the reaction solution was clarified, 2.3 kg of fumaric acid was added. After 2 hours of reaction, 30 L of ethyl acetate was added.Then the temperature was lowered to 0 to 5 ° C, and the crystals were stirred and crystallized for 3 to 4 hours. S3. Centrifuge the white powder of step S2 for 3 to 4 hours and place it in a 100L double cone vacuum dryer for vacuum drying.The initial drying temperature is 45 ° C, the degree of vacuum is ≤-0.08MPa, and the temperature is increased by 5 ° C every 4h. After drying for 12h,A white solid was obtained, namely amorphous tenofovir disoproxil hemifumarate. The amorphous tenofovir disoproxil hemifumarate prepared in this example has a purity of 99.32% and a solvent residue of 0.05%. The specific data are shown in Figures 1 and 2.
60.2 kg In ethanol at 30℃; for 3h; 1.S3-1.S4; 2.S3-2.S4; 3.S3-3.S4; 4 S3. Salt formation reaction:To the obtained tenofovir disoproxil solution of S2. Were added 5.39 kg of fumaric acid and 32.34 kg of absolute ethanol,Salt formation reaction at 30 ° C for 3 hours;S4. Preparation of tenofovir disoproxil hemifumarate: the reaction solution of step S3. Is concentrated under reduced pressure at 20 ° C. until there are no obvious droplets,To the concentrated system, add anhydrous ethanol to cool down to 0-10 ° C and crystallize, separate the crystals from the system with a centrifuge, and transfer the separated filter cake to a vacuum dryer.It is dried under reduced pressure at 40 to 60 ° C. for 12 to 16 hours to obtain 60.2 Kg of a white solid, that is, tenofovir disoproxil hemifumarate.The prepared tenofovir disoproxil hemifumarate was tested by HPLC to check its purity. Its total molar conversion is 85.54%

  • 27
  • [ 77-92-9 ]
  • [ 201341-05-1 ]
  • [ 1698012-72-4 ]
YieldReaction ConditionsOperation in experiment
In toluene at 60℃; for 0.166667h; 6 Example 6 Example 6 Preparation of Tenofovir disoproxil citrate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), stoichiometric equivalent of citric acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
  • 28
  • [ 50-21-5 ]
  • [ 201341-05-1 ]
  • [ 1698012-73-5 ]
YieldReaction ConditionsOperation in experiment
In toluene at 60℃; for 0.166667h; 9 Example 9: Preparation of Tenofovir disoproxil lactate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), stoichiometric equivalent of lactic acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
  • 29
  • [ 87-69-4 ]
  • tenofovir disoproxil [ No CAS ]
  • tenofovir disoproxil DL-tartaric acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
88.5% In isopropyl alcohol at 15 - 45℃; 2 Preparation of Tenofovir disoproxil DL-tartrate and its Form A At 40 ~ 45 ° C, tenofovir disoproxil 50.0g (96.3mmol) and DL-tartaric acid14.4g (95.9mmol) was dissolved in 4.5L isopropanol, dissolved completely cooled down to 15 ~ 20 ° C, stirring was continued crystallization; filtration; cake was dried under reduced pressure at 30 ~ 35 ° C, DL - Tenofovir disoproxil tartrate 57.0 g, yield 88.5%.
In toluene at 60℃; for 0.166667h; 10 Example 10 Example 10 Preparation of Tenofovir disoproxil tartarate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), stoichiometric equivalent of tartaric acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
  • 30
  • [ 201341-05-1 ]
  • [ 1197785-85-5 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid In toluene at 60℃; for 0.166667h; 8 Example 8: Preparation of Tenofovir disoproxil hydrogensulphate Oily crude Tenofovir disoproxil (1.5 g, 75% purity according to HPLC) was dissolved in toluene (3 mL), stoichiometric equivalent of sulphuric acid was added and mixture was heated to 60°C for 10 minutes. Then the solution was cooled to room temperature and stirred until precipitation occurred. The mixture was diluted using 5 mL of toluene and the suspension was filtrated and washed using 5 mL of toluene. The product was obtained in high yield and high purity.
  • 31
  • [ 500-05-0 ]
  • tenofovir disoproxil [ No CAS ]
  • tenofovir disoproxil coumalate [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In hexane; dichloromethane; at 20 - 40℃; In the container tenofovir disoproxil 3.0g and 0.8g <strong>[500-05-0]coumalic acid</strong> in a vessel and, after addition of methylene chloride 15 heated to 35C~40C and stirred to complete dissolution for 20 to 30 minutes. The dissolution the reaction solution after about 25C to gradually cooled slowly at 20C ~ 30C n-hexane was added 30 ml for 10 to 20 minutes. After stirring for 1-2 hours at about 25 by filtration and the reaction solution (mother liquor) and the drying hunpung while washing the filtered crystals as n- hexane 10 crystal obtained by filtration at about 40 the objective compound gained: tenofovir disoproxil kumal rate 3.39g (89.0% yield)
  • 32
  • [ 35180-01-9 ]
  • [ 206184-49-8 ]
  • [ 201341-05-1 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In diethyl ether; N,N-dimethyl-formamide at 20 - 57℃; for 8h; 1 1. Esterification: 1000ml 400ml reaction flask in ether, 50ml of dimethylformamide and 40g tenofovir monohydrate open stirring, temperature control of triethylamine was added dropwise at 67g 20 , dropwise at 71/92 chloroformate 100g carbonate, isopropyl after dropping the reaction system was raised to 57 incubated for 8 hours, detection reaction monoester less than 10%, the reaction solution was concentrated under reduced pressure below 40 without liquid to flow out to the concentrated raffinate 500ml of ethyl acetate was added, 200ml6% sodium bicarbonate solution, stirred and extracted stratification, the organic phase was washed twice with 200ml of water continues purified and the resulting organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, the resulting residue was concentrated It was used directly in the next step.
  • 33
  • [ 2102893-66-1 ]
  • [ 201341-05-1 ]
YieldReaction ConditionsOperation in experiment
99.9 %Chromat. With sodium carbonate In methanol; dichloromethane; water for 0.166667h; 1 Tenofovir disoproxil free base new crystalline form manufacture At a room temperature, 200 g of the Tenofovir disoproxil fumarate (chinese Asta chemical) was dissolved in 3.6 L of methylene chloride and 360 mL of methanol. 10% aqueous sodium carbonate solution was added and stirred for 10 minutes, the pH was adjusted to about 9-10 and the organic layer was separated. Water was removed from the organic layer using magnesium sulfate, followed by filtration and concentration under reduced pressure at 45 ° C. Thereafter, 600 ml of isopropyl alcohol was added, followed by stirring at 24 ° C for 2 hours, followed by filtration (washing with 200 ml of isopropyl alcohol) and 140 g of the Tenofovir disoproxil base new crystalline form was obtained (melting point (mp): 106, and purity (Purity): 99.90%).
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