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CAS No. : | 78-40-0 | MDL No. : | MFCD00009077 |
Formula : | C6H15O4P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DQWPFSLDHJDLRL-UHFFFAOYSA-N |
M.W : | 182.15 | Pubchem ID : | 6535 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.87 |
TPSA : | 54.57 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.84 cm/s |
Log Po/w (iLOGP) : | 2.69 |
Log Po/w (XLOGP3) : | 0.8 |
Log Po/w (WLOGP) : | 2.2 |
Log Po/w (MLOGP) : | 0.35 |
Log Po/w (SILICOS-IT) : | 0.78 |
Consensus Log Po/w : | 1.37 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.08 |
Solubility : | 15.2 mg/ml ; 0.0837 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.53 |
Solubility : | 5.41 mg/ml ; 0.0297 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.5 |
Solubility : | 5.83 mg/ml ; 0.032 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.84 |
Signal Word: | Danger | Class: | N/A |
Precautionary Statements: | P301+P330+P331-P312-P302+P352-P337+P313-P201-P280 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H340-H351 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | at 130℃; for 24 h; | A mixture of ethyl 2-bromo-2-fluoroacetate (2.5 g, 13.5 mmol) and triethyl phosphate (5.8 mL, 32.8 mmol) was heated at 130°C for 24 hr. The excess of triethyl phosphate was removed by distillation under reduced pressure to afford ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (473-1) (3.0 g, 92percent yield) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | at -5 - -1℃; for 15 h; | Fludarabine (10g), triethyl phosphate (90mL), phosphorus oxychloride (6mL) were placed under stirring -5~-10°C low temperature circulating pump, while maintaining the internal temperature -5 ~ -1 ° C; stirring reaction at -5 ~ -1 ° C for 15 hours; when the amount of fludarabine in the HPLC detection area, less than 2percent is considered The reaction was completed, then pure water (50 mL) was added to the obtained mixture under stirring, and washed with dichloromethane. The obtained aqueous phase was adjusted to pH=3 with 50percent NaOH solution, concentrated under reduced pressure at 35-40 ° C, and recrystallized. Filtration, the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was dried under vacuum at 45-50 ° C for 10-12 hours to obtain a crude product of fludarabine phosphate having a purity of 99.2percent and a yield of 73.3percent.The crude fludarabine phosphate obtained by the above preparation method is added to 100 mL of pure water at room temperature, stirred uniformly, and 50percent NaOH solution is slowly added dropwise until completely dissolved, and the filtrate is added dropwise to a dilute hydrochloric acid solution at room temperature with a white solid. Precipitate,After suction filtration, the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was vacuum-dried at 45-50 ° C for 10-12 hours to obtain fludarabine phosphate. The purity was 99.9percent, and the yield was 96.5. percent. |
81.02% | Stage #1: at -6℃; for 0.333333 h; Stage #2: for 12 h; |
To a 500 mL flask was added 20 g of fludarabine followed by 200 mL of triethyl phosphate, and the flask was placed at a low temperature of -6 ° CReaction bath, 20min after slowly dropping phosphorus oxychloride 20mL (side drop while stirring), the reaction 12 hours (TCL tracking). Reaction reachedTo the request after the flask quickly add 80mL water and 200mL dichloroethane, standing for 30 minutes after the extraction of water and organic phase, the waterAdjust the pH value to 2-3. Recrystallization white floc with a Buchner funnel filter, vacuum dry weighing a white powder20.71 g, yield 81.02percent, HPLC mass fraction 99.95percent, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | at 180℃; for 8 h; | The 9,10-Bis(bromomethyl)anthracene (1.2 g, 3.3 mmol) was mixed with triethyl phosphate (10 mL). Resulting mixture was refluxed at 180°C for 8 h in order to obtain the pure product. The solvent was then removed at vacuum and the residue product was purified by a column chromatography on silica gel using ethyl acetate/CH2Cl2 as the eluent. Yield: 1.05 g (68percent). 1H NMR (300 MHz, CDCl3): δ 8.38 (m, 4H), δ 7.6 (m, 4H), 4.25 (d, 4H), 3.8 (m, 8H), 1.06 ppm (t, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.2% | With phosphorous; oxygen; copper dichloride In benzene at 50℃; | |
98.2% | With phosphorous; oxygen; copper dichloride In benzene at 50℃; other alkylalcohols, var. concentrations of reagents; | |
97.7% | With trichlorophosphate In acetone at 10 - 30℃; for 4h; | 8 In a 2L to of the three-port flask 368.56g, 8mol ethanol, then adding acetone 92.9g, 1 . 6mol, after stirring and mixing cooling to 10 °C the following, stirring next adds by drops 245.33g, 1 . 6mol phosphorus oxychloride, control the mixture temperature is not higher than 10 °C.50 minutes after the dropping. Stirring 10 minutes, under the condition of vacuum heating to 30 degrees, the vacuum degree 10mmHg, reaction 3h, the end of the reaction, adding containing 12.5g ethanol the sodium is mellow solution, stirring for one hour, water after cooling, dissolve, produce sodium chloride, separating, collecting the organic phase, the organic phase washed to neutral, moisture is removed by reduced pressure distillation and low-boiling ethanol and acetone, the purity is not less than 96% triethyl phosphate product the ester is thick 292.4g, the fractionating column, pressure reducing fractionated 285.6g triethyl phosphate, yield 97.7%, purity ≥ 99.5%. |
92% | With phosphorous; tetraethylammonium iodide In water; acetonitrile at 50℃; Electrolysis; | |
75% | With black phosphorus; dihydrogen peroxide at 40℃; for 4h; Green chemistry; | 1 Example 1: Synthesis of Triethyl Phosphate Method 1 6.2 mg of black phosphorus crystals were dispersed in 20 mL of ethanol, 2 mL of H2O2was added dropwise to the system, and thereaction was stirred at 40 ° C for4 h. After the solution was clarified, the reaction was stopped, followed by rotary evaporation to remove the solvent, followed by silica gel column chromatography. The yellow oily product,triethyl phosphate, was obtained in a yield of 75%. |
72% | With phosphorous; tri(p-bromophenyl)amine; N,N,N,N-tetraethylammonium tetrafluoroborate In acetonitrile at 53℃; electrolysis; | |
With trichlorophosphate | ||
With pyridine; ammonia; trichlorophosphate | ||
With pyridine; trichlorophosphate | ||
With phosphorus pentoxide | ||
With hydrogenchloride; zinc(II) phosphide; oxygen at 39.9℃; | ||
With zinc(II) phosphide; oxygen; lithium chloride; copper dichloride at 39.9℃; Yield given; | ||
With pyridine; trichlorophosphate In benzene for 2h; Heating; | ||
With hydrogenchloride; zinc(II) phosphide; oxygen at 39.9℃; ΔE(excit.), ΔS(excit.); | ||
With hydrogenchloride; zinc(II) phosphide; copper dichloride at 39.9℃; other additive; Ea; ΔS(excit.); other alcohols; | ||
With sodium hexachloroplatinate; phosphan at 25 - 40℃; | ||
With pyridine; trichlorophosphate In benzene at 0 - 5℃; | ||
100 % Chromat. | With pyridine; iodine; phosphan at 50℃; | |
With pyridine; ammonia; trichlorophosphate | ||
With pyridine; sodium carbonate; trichlorophosphate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Diethyl 2-thienylmethylphosphonate (7). A mixture of 2-chloromethylthiophene 6 (183.6 g, 1385 mmol) and triethyl phosphate (241.5 g, 1454 mmol) was heated at 140-145 C. for 3 hours, the resulting liquid was cooled to 120 C. before nitrogen bubble was blown underneath the surface for 1.5 hours. The liquid was cooled to room temperature to afford 324 g of product and was used in the subsequent reaction without further purification (99%). 1H NMR (CDCl3) delta 7.38 (dd, J=4.8, 0.8 Hz, 1H), 7.14-7.18 (m, 1H), 6.90-7.00 (m, J=5.1, 1H), 4.03 (q, J=7.3 Hz, 4H), 3.40 (s, 1H), 3.30 (s, 1H) Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation of [CF3 (CF213CH2CH2LO-3H2] A mixture of 37.4 g of [1-IODO-LH, LH,] 2H, [2H-PERFLUOROHEXANE] and 50.0 g of triethyl phosphite was heated at [150 °C.] After 16 hr, an additional 50.0 g of triethyl phosphite was added, and heating was continued. After 2 hr, an additional 50.0 g of triethyl phosphite was again added, and heating was continued for another 24 hr. Diethyl ethylphosphonate and other volatiles were removed by distillation through a 12-inch (30 cm) vacuum- jacketed packed column, b. p. [34-38 °C] at 0.05 torr (7 Pa). Distillation of the concentrate provided 22.3 g of [1-DIETHYLPHOSPHONO-LH, LH,] 2H, 2H-perfluorohexane as a 90: 2: 7 mixture with triethyl phosphate and ethyl 1H, lH, 2H, 2H-perfluorohexyl ethylphosphonate as a clear, colorless liquid, b. p. [47-51 °C] at 0.05 torr (7 Pa). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | at 20 - 120℃; for 1h; | Triethyl phosphite (1 ml) was added to <strong>[105942-09-4]4-cyano-2-fluorobenzyl bromide</strong> (100 mg, 0.467 mmol), a compound known in literature, at room temperature under a nitrogen atmosphere, and the resulting mixture was adjusted to 120C. After 1 hour, the reaction solution was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluents: hexane/ethyl acetate and chloroform/ethyl acetate) to obtain diethyl (4-cyano-3-fluorobenzyl)phosphonate (120.6 mg, 95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydroxide; In methanol; ethanol; water; cyclohexanone; toluene; | Example 2 Synthesis of Ipidacrine (i.e. 9-Amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline) 394 g (2774 mmol) of diphosphorus pentaoxide (P2O0) was suspended in 500 ml of toluene and raised in temperature to 55° C. At that temperature, 283 ml (1665 mmol) of triethyl phosphate was added dropwise, then 75 ml (1295 mmol) of ethanol was added dropwise and the resultant mixture was stirred for 30 minutes. The solution was cooled to 30° C., 50 g (462 mmol) of <strong>[2941-23-3]2-amino-1-cyclopentene-1-carbonitrile</strong> and 50 ml (485 mmol) of cyclohexanone were added, then the solution was stirred at 55° C. for 3.5 hours. The heating was stopped, 500 ml of water was added dropwise at not more than 55° C., and the solution was stirred at 55° C. for 30 minutes. The aqueous phase was separated and the toluene phase was washed by 250 ml of water. The resultant aqueous phase was combined with the previously separated aqueous phase. The aqueous phase was added dropwise into 2000 ml of an 18percent sodium hydroxide aqueous solution, then the precipitated crystal was collected by filtration and rinsed well. The hydrous crystal obtained was dissolved by heating to a mixed solvent of 750 ml of methanol and 1500 ml of water and the resultant solution was cooled for recrystallization. The precipitated crystal was filtered, rinsed, then dried in vacuo at 60° C. to obtain 79 g (420 mmol) of the desired compound as an anhydride. The yield was 91percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In tetrahydrofuran; | EXAMPLE 32 Potassium diethylphosphate The procedure of Example 1 was followed except that triethylphosphate (3.4 mL, 20 mmol) was added by syringe to a slurry of <strong>[10519-96-7]potassium trimethylsilanolate</strong> (2.56 g, 20 mmol) in dry tetrahydrofuran (50 mL), and a 2 h reaction time at room temperature was used, followed by 40 h of heating at reflux. Potassium diethylphosphate (3.55 g, 92% yield) was isolated as a white solid: 1 H NMR (D2 O, DSS) delta 1.1 (t, J=6.9 Hz, 6H), 3.75 (q, J=6.9 Hz, 4H). Anal. Calcd. for C4 H10 KO4 P: C, 25.00; H, 5.24; K, 20.34. Found: C, 25.83, 25.88; H, 5.40, 5.29; K, 20.37, 20.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; | EXAMPLE II 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate (R=H2 PO3 --) 9-beta-D-Arabinofuranosyl-2-fluoroadenine (2.6 g, 9.1 mmol) was added to 23 ml of triethylphosphate containing POCl3 (4.6 g, 30 mmol) held at 0, and the mixture was stirred for 31/2 hours before it was poured into 200 ml of ice water. The pH of the solution was adjusted to 2 with 6 N NaOH before it was extracted with CHCl3 (2*180 ml) and then slurried with charcoal (40 g) and Celite (20 g) for 20 min. The solids were removed by filtration and washed with water until free of acid. The product was extracted with a mixture of SOEtOH:NH2 OH:9H2 O. The basic solution was lyophilized to give the product 3.46 g. Some of this material was converted to the free acid by means of a Domex 1*8 (formate form) column. UVmax (e*10-3): 262 (13.5), pH 7-262 (15.5), pH 13-261 (15.2). Anal. Calcd. for C10 H13 FN5 O7 P.3/4H2 O: C, 31.71; H, 3.86; N, 18.49. Found: C, 32.00; H, 3.86; N, 18.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.8% | With sodium hydroxide; trichlorophosphate In water at -15 - 0℃; for 2.5h; Large scale; | 3 Synthesis of arabinosyladenosine monophosphate: 1. Prepare a 40% aqueous sodium hydroxide solution: Add 37.5kg of purified water to the 50L reactor.15.0 kg of sodium hydroxide was added in portions under stirring and stirred for dissolution and use. 2. Add 200-L reaction tank to β-D-adenosine10.0kg,Triethyl phosphate 100.0 kg, cooled to -15°C . 3. Add phosphorus oxychloride 10.2kg under stirring, and control the temperature no higher than 0°C.Dropping is completed within 3 to 5 hours;After the addition is complete, the reaction is stirred at -0°C for 150 minutes.TLC detected that the reaction reached the end and stopped the reaction.Phosphorus oxychloride is added dropwise with stirring10.2kg, control temperature is not higher than 0°C. 4. The reaction solution was slowly pumped into a 500 L reaction tank (containing 150 kg of purified water pre-frozen to 2°C).The control temperature is not higher than 15°C. 5, cooling to 0 °C, adding 40% NaOH aqueous solution, adjust the pH to 2.0, control the temperature is not higher than15°C. 6. Add 67kg of dichloromethane to extract 3 times. Combine the aqueous phase. Add 0.5kg of activated carbon to the aqueous phase and decolorize for 30min.Activated carbon was filtered out, the temperature was controlled below 15 °C, the mass fraction of 40% NaOH aqueous solution was slowly adjusted to pH 2.5; 7, cooling to 15 °C, standing crystal 12h. 8. Centrifugation, washing the filtered crystals with 10 kg of cold purified water (about 15° C.) to obtain adenosine monophosphate wet crude product. Refinement of adenosine monophosphate. 1. Prepare an aqueous sodium hydroxide solution with a mass fraction of 40%: Add 20ml of purified water to the reactor and stirAdd 5.0 kg of sodium hydroxide in portions and stir and dissolve for later use. 2. Prepare hydrochloric acid aqueous solution with 10% mass fraction: Add 20kg of purified water to the reactor with a mass fraction of36% concentrated hydrochloric acid 5kg, stir and mix until use. 3. Add 200L of purified water and the above-mentioned monophosphate adenosine wet crude product in a 200L reaction vessel, and mix the mass fraction under stirring.A 40% aqueous solution of sodium hydroxide adjusted the pH in the kettle to 7. 4. Add 500g of activated carbon, stir and decolorize for 30 minutes, filter by 0.45μm plate and frame filter and then 0.22μm plateThe frame filter was pressed into a 500 L crystallization tank, and a 10% by mass aqueous solution of hydrochloric acid was added dropwise. The temperature was adjusted to 15° C. and the pH was slowly adjusted to 2.5. 5, the above liquid cooling to 15 °C, standing crystal 12h. 6. Centrifugal, purified water 10kg (about 15 °C) and 30kg absolute ethanol, vacuum drying (55 °C, vacuum degree ≥-0.085 MPa, 10 hours), crushed and weighed to give an off-white solid, namely adenosine monophosphate.The total molar yield is 87.80% (based on β-D-adenosine)The selectivity is 90.2% and the purity is 99.9%. |
With trichlorophosphate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol | 3 EXAMPLE 3 EXAMPLE 3 To 100 ml. of triethyl phosphate was added 10.69 g. (0.04 mole) of anhydrous 9-(β-D-arabinofuranosyl)adenine in one portion with stirring. This mixture was cooled in an ice bath to 2° C. and 9.20 g. (0.06 mole) of phosphorus oxychloride was then added during a three-minute period, the temperature rising to about 4° C. The reaction mixture was stirred in the cold for 2 hours 30 minutes, after which the clear solution was poured into 80 g. of ice. This mixture was stirred in an ice bath to maintain a temperature below 10° C. while the pH was adjusted to 2 using 50% sodium hydroxide solution. The resulting turbid mixture was extracted twice using 100-ml. and 50-ml. portions of dichloromethane and the aqueous layer was again adjusted to pH 2 using additional caustic. After seeding, this solution was placed in the refrigerator overnight to give a dense white precipitate. This was stirred with a glass rod and again allowed to stand overnight in the cold. The white product was filtered and washed using 22 ml. of ice water, 35 ml. of cold 50% ethanol and 25 ml. of cold absolute ethanol. After drying in vacuo at 40° C., 9.60 g. (69.1% of theory) of the product, 9-(β-D-arabinofuranosyl)adenine, 5'-phosphate, was obtained which assayed as follows: The corrected yield of 9-(β-D-arabinofuranosyl)adenine, 5'-phosphate was therefore 62.1% of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2h; | 3.A Example 3. Preparation of (15,S5)-(l-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-θ-phosphonooxy-hexylcarbamoylj-l-naphthalen-l-yl-ethyty-carbamic acid methyl ester (PL-507) The preparation of the title compound is based on scheme 2 A of this invention. Step A. Preparation of (lS)-(4-[5-tert-butoxycarbonylamino-l-(diethoxyphosphoryloxymethyl)-pentyl]-isobutyl-sulfamoyl}-phenyl)-carbamic acid tert- butyl ester (VIII) 2.00 g (3.7 mmol) (lS)-{4-[(5-tert-butoxycarbonylamino-l-hydroxymethyl-pentyl)-isobutyl- sulfamoyl] -phenyl }-carbamic acid tert-butyl ester (VII) (example IA, step D) is dissolved in 0.63 mL triethylphosphate and 10 mL THF at 0 0C under inert argon atmosphere. 0.63 mL (4.44 mmol) diethylchlorophosphate is added and then 0.25 g (6.2 mmol), NaH 60% in oil is added in portionwise. The mixture is allowed to warm to room temperature and left to stir for 2 h (LC-MS showed completion after 1 h). To the solution is added 20 mL of Amberlite XAD-2 resin and the slurry thoroughly mixed and added to 200 mL ice water. After stirring for 15 min. the resin suspension is filtered and the resin washed several times with distilled water (500 mL). The desired product is desorbed from the resin with acetone (5 X 50 mL), EtOAc (5 X 50 mL), the organic phase is then dried over Na2SO4. After evaporation of the solvent 2.66 g (89%) of clear oil is obtained. The crude product contains a fraction with two diethyl phosphates and is used as is in the next step. 1H NMR (CD3OD): δ 0.91 (d, J = 6.3, 6H), 1.11-1.21 (m, 2H), 1.33 (t, J = 6.9, 10H), 1.43 (s, 9H), 1.53 (s, 10H), 1.90-1.97 (m, IH), 2.88-2.96 (m, 3H), 2.96-3.04 (m, IH), 3.81-3.90 (m, IH), 3.91-3.99 (m, IH), 4.01-4.14 (m, 4H), 7.61 (d, J = 8.3, 2H), 7.72 (d, J = 8.4, 2H).31 P NMR (CD3OD): S 1.59 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In not given PO(OC2H5)3 dropwise addn. to Ca acetate, stirring (25-30°C, 12 h,40-45°C, 12 h), gelation on heating (75°C, 10 h), drying, heat treatment (1000°C); influence of alcohol addition studied; stirring (aq. HCl), washing (water); X-ray diffraction; | ||
With ethanol In not given PO(OC2H5)3 dropwise addn. to Ca acetate, ethanol addn., stirring (25-30°C, 12 h, 40-45°C, 12 h), gelation on heating (75°C,10 h), drying, heat treatment (1000°C); influence of alcohol add ition studied; stirring (aq. HCl), washing (water); X-ray diffraction; | ||
With methanol In not given PO(OC2H5)3 dropwise addn. to Ca acetate, methanol addn., stirring (25-30°C, 12 h, 40-45°C, 12 h), gelation on heating (75°C, 10 h), drying, heat treatment (1000°C); influence of alcohol addition studied; stirring (aq. HCl), washing (water); X-ray diffraction; |
With propan-1-ol In not given PO(OC2H5)3 dropwise addn. to Ca acetate, propanol addn., stirring (25-30°C, 12 h, 40-45°C, 12 h), gelation on heating (75°C, 10 h), drying, heat treatment (1000°C); influence of alcohol addition studied; stirring (aq. HCl), washing (water); X-ray diffraction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | at 120℃; for 3.0h; | To 4-(bromomethyl)-1 -methoxy-2-nitrobenzene (10 g, 40.9 mmol ) was added triethyl phosphate (10.5 g, 63 mmol). The reaction was heated at 120 C for 3 h and purified by chromatography to afford the desired compound as colorless oil (9.0 g, 72%) <n="125"/>MS [(+), m/z]: 304 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; toluene; | Next, a mixed solution of 2.0 g of 9-(2-nitrophenyl)phenanthrene and 40 ml of triethyl phosphate was heated and stirred under a nitrogen gas stream at 150 C. for 8 hours. After cooling to room temperature, 50 ml of water was poured into the solution, followed by extraction with 50 ml of toluene. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then concentrated by evaporation. The concentrate was purified by silica gel chromatography and then vacuum-dried to obtain 840 mg of 13H-13-azaindeno[1,2-l]phenanthrene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In water at 130℃; for 14h; | Inventive Examples El and E2 Triethylphosphate (929 g, 5.0 mole) was added dropwise over 2 hours to a reaction vessel containing N-methylimidazole (411 g, 5.0 mole) and water (El: 50 mL; E2: 100 mL). Afierwards the reaction mixture was heated up to 130° C. and stirred under reflux for 14 h. Then, the volatile parts were removed under reduced pressure with a rotary evaporator. In each case, 1 -ethyl-3-methylimidazole diethylphosphate was obtained in 99% yield. |
97.3% | at 100℃; for 36h; | Synthesis of 3-Ethyl-1-methylimidazoliumDiethyl Phosphate (IL2) A mixture of 1-methylimidazole (100 mL, 1.25 mol) andtriethylphosphate (235 mL, 1.38 mol) was heated at 1008C for36 h. After cooling to room temperature, the reaction mixturewas washed with diethyl ether and the recovered liquid wasfurther purified by hydrodistillation for 4 h. The recoveredyellowish liquid (3.22 g, 97.3 %) was characterised by1H NMR and 13C NMR analysis.dH (250 MHz, D2O) 9.87 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H),4.23 (q, 2H), 3.89 (s, 3H), 3.64 (m, 4H), 1.40 (t, 3H), 1.05 (t, 6H).dC (63 MHz, D2O) 136.9, 123.5, 121.9, 58.9, 43.9, 35.5,16.6, 15.1. |
at 140℃; Inert atmosphere; |
at 150℃; for 15h; Inert atmosphere; | ||
at 120℃; for 0.333333h; Microwave irradiation; | ||
In acetonitrile at 0℃; | ||
at 80 - 150℃; for 18h; | ||
at 2899.99℃; for 24h; Sealed tube; Darkness; | 2.2. Synthesis of the [EMIm][DEP] 1-Ethyl-3-methylimidazolium diethylphosphate (CAS number848641-69-0; purity N 98%) was synthesized at QUILL (Queen's UniversityIonic Liquid Laboratories) by following the methodology reportedbelow which is comparable to that reported originally in the literature[21,22]. Briefly, N-methylimidazole (8.2 g, 0.1 mol) and an equimolaramount of triethyl phosphate (18.2 g, 0.1 mol) were added to a Cariustube and flushedwith nitrogen. After sealing and covering in aluminumfoil the tube was then heated to 373.15 K for 24 h. The resulting liquidwas washed with diethyl ether (3 × 20 cm3) at room temperaturefollowed by drying under reduced pressure (1 Pa) at 353 K overnightto remove starting materials and solvent residues. After washing anddrying the ionic liquid resulting yield was 21.9 g, 83%. Before measurements,the sample was again dried and degassed under low pressure(1 Pa) at temperatures not exceeding 373 K. IL was kept under a nitrogenatmosphere and then usedwithout any further purification. The purityof the samplewas firstly estimated by considering thewater level inthe sample (lower than 0.01 wt/wt% (or 100 ppm) by Karl Fischer Coulometrictitration using an 899 Coulometer, Metrohm) and by comparing 1H and 13C NMR spectra recorded at 293 K on a BrukerAvance DPX spectrometer at respectively 300 MHz and 75 MHz withthose published by either Kuhlmann et al. [22] or Hiraga et al. [23] asshown in the Figs. S1 and S2 of the supporting information (SI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 150℃; for 15h; Inert atmosphere; | ||
28.5 kg | at 150℃; for 12h; Large scale; | 4.1 Example 4 (1) 10.81 kg of N-allylimidazole was added, and 18.21 kg of triethyl phosphate was added thereto. The reaction was stirred at 150 ° C for 12 hours, washed with ethyl acetate and steamed at 80 ° C to obtain 28.5 kg1-allyl-3-ethyl imidazolium phosphate, For the light yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 160℃; for 4h; | |
95% | at 120℃; for 10h; | The procedure for the preparation of diethyl 3,5-dimethoxybenzylphosphonate (4) The mixture of 3 (43.4g, 188mmol) and triethyl phosphate (90 ml) were heated at 120 for 10h. The excess triethyl phosphate was removed in vacuum and the crude product was purified by silica gel column chromatography (EtOAc/petroleum ether 1 : 3) to give the title compound as an oil (yield 95% ). 1H NMR (400 MHz, CDCl3) δ 6.46 (d, J = 2.1 Hz, 2H), 6.35 (d, J = 1.9 Hz, 1H), 4.05-4.02 (m, 4H), 3.77 (s, 6H), 3.08 (dd, J = 21.6, 5.9 Hz, 2H), 1.28-1.23 (m, 6H). |
95% | at 160℃; for 4h; |
at 135℃; for 7h; | ||
With tetrabutylammomium bromide at 150℃; for 6h; | ||
at 120℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: triethyl phosphate With pyridine; trifluoromethylsulfonic anhydride In dichloromethane at 20℃; for 0.166667h; Stage #2: phenol In dichloromethane at 20℃; for 0.5h; | |
92% | Stage #1: triethyl phosphate With pyridine; trifluoromethylsulfonic anhydride In dichloromethane at 20℃; for 0.166667h; Stage #2: phenol In dichloromethane at 20℃; for 0.5h; | 1.c c. GENERAL PROCEDURE FOR THE SYNTHESIS OF PHOSPHATE DERIVATIVES [00385] Diethyl phenyl phosphate (3a'): To a solution of triethyl phosphate la (36.4 mg, 0.2 mmol), Tf20 (50.5 μ, 0.3 mmol) in DCM (1.0 mL) was added pyridine (32 μ, 0.4 mmol) in a 2-dram vial with a PTFE cap. After stirring for 10 min, phenol (38.1 mg, 0.4 mmol) was added to the reaction mixture. After stirring for another 30 min at room temperature, the resulting mixture was concentrated to give the crude product which was then purified by column chromatography on silica gel (PE/EA = 3: 1) to afford ethyl phenyl benzylphosphonate (3a'). i. ETHYL PHENYL BENZYLPHOSPHONATE (3 A')3a'[00386] 42.3 mg, 92%; as a colorless oil; Rf= 0.20 (vHexane vEA = 2: 1); NMR (400 MHz, CDCh) δ 7.37-7.30 (m, 2H), 7.24-7.20 (m, 2H), 7.19-7.14 (m, 1H), 4.28-4.15 (m, 4H), 1.35 (td, J= 7.2, 1.2 Hz, 6H);13C NMR (100.5 MHz, CDCh) δ 150.8, 129.6, 124.9, 1 19.9 (d, J= 4.4 Hz), 64.5 (d, J= 5.9 Hz), 16.0 (d, J= 6.7 Hz); Spectroscopy data of the compound match with the data reported in the corresponding reference (Panmand et al. (2014)Tetrahedron Lett. 55: 5898-5901). |
78% | With phosphorus pentoxide at 120℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In water at 20℃; for 0.683333h; Sonication; Green chemistry; | 4. General procedure for synthesis of α-aminophosphonates General procedure: Aldehydes (1.0 mmol), amines (1.0 mmol), and triethyl phosphate(1.0 mmol) were put into a 25ml round-bottomedflask in ethyl lactate/water (3:2, 3 ml). The reaction flask waslocated in the ultrasonic bath and irradiated at room temperaturefor the appropriate time. After completion of thereaction as indicated by TLC, the mixture was extractedwith ethyl acetate (10 ml ×3). The combined organic phasewas dried over anhydrous Na2SO4 and the solvent wasremoved under reduced pressure. The residue was then subjectedto preparative TLC to give pure product by usingmixed ethyl acetate and petroleum ether as an eluent. |
91% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.416667h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.5h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.5h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.5h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
94% | In water at 20℃; for 0.666667h; Sonication; Green chemistry; | 4. General procedure for synthesis of α-aminophosphonates General procedure: Aldehydes (1.0 mmol), amines (1.0 mmol), and triethyl phosphate(1.0 mmol) were put into a 25ml round-bottomedflask in ethyl lactate/water (3:2, 3 ml). The reaction flask waslocated in the ultrasonic bath and irradiated at room temperaturefor the appropriate time. After completion of thereaction as indicated by TLC, the mixture was extractedwith ethyl acetate (10 ml ×3). The combined organic phasewas dried over anhydrous Na2SO4 and the solvent wasremoved under reduced pressure. The residue was then subjectedto preparative TLC to give pure product by usingmixed ethyl acetate and petroleum ether as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.416667h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.25h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
95% | In water at 20℃; for 0.666667h; Sonication; Green chemistry; | 4. General procedure for synthesis of α-aminophosphonates General procedure: Aldehydes (1.0 mmol), amines (1.0 mmol), and triethyl phosphate(1.0 mmol) were put into a 25ml round-bottomedflask in ethyl lactate/water (3:2, 3 ml). The reaction flask waslocated in the ultrasonic bath and irradiated at room temperaturefor the appropriate time. After completion of thereaction as indicated by TLC, the mixture was extractedwith ethyl acetate (10 ml ×3). The combined organic phasewas dried over anhydrous Na2SO4 and the solvent wasremoved under reduced pressure. The residue was then subjectedto preparative TLC to give pure product by usingmixed ethyl acetate and petroleum ether as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.333333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
94% | In water at 20℃; for 0.416667h; Sonication; Green chemistry; | 4. General procedure for synthesis of α-aminophosphonates General procedure: Aldehydes (1.0 mmol), amines (1.0 mmol), and triethyl phosphate(1.0 mmol) were put into a 25ml round-bottomedflask in ethyl lactate/water (3:2, 3 ml). The reaction flask waslocated in the ultrasonic bath and irradiated at room temperaturefor the appropriate time. After completion of thereaction as indicated by TLC, the mixture was extractedwith ethyl acetate (10 ml ×3). The combined organic phasewas dried over anhydrous Na2SO4 and the solvent wasremoved under reduced pressure. The residue was then subjectedto preparative TLC to give pure product by usingmixed ethyl acetate and petroleum ether as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.583333h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.5h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With phosphotungstic acid supported on imidazole functionalized silica coated cobalt ferrite nanoparticle In neat (no solvent) at 20℃; for 0.25h; | General procedure of catalytic α-aminophosphonates synthesis General procedure: A mixture of an aldehyde (1 mmol), aniline (1 mmol), triethyl phosphate or trimethyl phosphate (1.2 mmol) and PTA/Si-imid(at) Si-MNPs catalyst (0.05 g) was stirred for an appropriate time at room temperature. The progress of the reaction was monitored by TLC. At the end of the reaction, CH3Cl was added to dilute the reaction mixture and the organic layer was simply decanted by means of an external magnet. The isolated solution was purified on a silica-gel plate to obtain pure product. The identities of the products were confirmed by FT-IR and 1H NMR spectral data |
94% | In water at 20℃; for 0.483333h; Sonication; Green chemistry; | 4. General procedure for synthesis of α-aminophosphonates General procedure: Aldehydes (1.0 mmol), amines (1.0 mmol), and triethyl phosphate(1.0 mmol) were put into a 25ml round-bottomedflask in ethyl lactate/water (3:2, 3 ml). The reaction flask waslocated in the ultrasonic bath and irradiated at room temperaturefor the appropriate time. After completion of thereaction as indicated by TLC, the mixture was extractedwith ethyl acetate (10 ml ×3). The combined organic phasewas dried over anhydrous Na2SO4 and the solvent wasremoved under reduced pressure. The residue was then subjectedto preparative TLC to give pure product by usingmixed ethyl acetate and petroleum ether as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With pyridine; carbon tetrabromide In dichloromethane at 0 - 20℃; for 9h; | 54 Synthesis of Compound 54 Phorbaketal A (12mg, 0.03mmol) and carbon tetrabromide (20mg, 0.36mmol), together with pyridine (0.5ml), were mixed with triethylphosphate (12µℓ, 0.075mmol) in anhydrous dichloromethane (5ml) at 0°C, and the mixture was allowed to react at room temperature for 9 hours. The reaction liquid was washed with 10% HCl and an aqueous saturated NaHCO3 solution, and then the layer separation was carried out by using water and dichloromethane. The organic solvent layer was dried over Na2SO4. Purification using column chromatography was conducted to obtain Compound 54 (10mg, 63%). MS m/z 534 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With pyridine; carbon tetrabromide In dichloromethane at 0 - 20℃; for 9h; | 54 Synthesis of Compound 54 Phorbaketal A (12 mg, 0.03 mmol) and carbon tetrabromide (20 mg, 0.36 mmol), together with pyridine (0.5 ml), were mixed with triethylphosphate (12 μl, 0.075 mmol) in anhydrous dichloromethane (5 ml) at 0° C., and the mixture was allowed to react at room temperature for 9 hours. The reaction liquid was washed with 10% HCl and an aqueous saturated NaHCO3 solution, and then the layer separation was carried out by using water and dichloromethane. The organic solvent layer was dried over Na2SO4. Purification using column chromatography was conducted to obtain Compound 54 (10 mg, 63%). MS m/z 534 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: methyl 2-(benzyloxycarbonylamino)-2-methoxyacetate With phosphorus tribromide In toluene at 70℃; for 20h; Stage #2: triethyl phosphate In toluene at 70℃; for 2h; | 20.20-3 Step 20-3. Meth l 2-(benzyloxycarbonylamino)-2-(diethoxyphosphoryl)acetate (20d) Step 20-3. Meth l 2-(benzyloxycarbonylamino)-2-(diethoxyphosphoryl)acetate (20d) 20 c 20d To a solution of 20c (12 g, 47.4 mmol) in toluene (60 mL) was added PBr3 (12.8 g, 47.4 mmol) at 70 °C, the reaction was stirred at 70 °C for 20 h, then triethyl phosphate (7.87 g, 47.4 mmol) was added dropwise and stirred at 70 °C for another 2 h. The mixture was concentrated, diluted with EtOAc, and washed with sat. NaHC03 aq.. The organic layers were dried over anhydrous Na2S04, filtered and concentrated. The resulting residue was dissolved in EtOAc, petroleum ether was added with vigorous stirring, then filtrated to give 20d as a white solid (8 g, yield: 47%). |
47% | Stage #1: methyl 2-(benzyloxycarbonylamino)-2-methoxyacetate With phosphorus tribromide In toluene at 70℃; for 20h; Stage #2: triethyl phosphate In toluene at 70℃; for 2h; | 20-3 Methyl 2-(benzyloxycarbonylamino)-2-(diethoxyphosphoryl)acetate To a solution of 20c (12 g, 47.4 mmol) in toluene (60 mL) was added PBr3 (12.8 g, 47.4 mmol) at 70 °C, the reaction was stirred at 70 °C for 20 h, then triethyl phosphate (7.87 g, 47.4 mmol) was added dropwise and stirred at 70 °C for another 2 h. The mixture was concentrated, diluted with EtOAc, and washed with sat. NaHC03 aq.. The organic layers were dried over anhydrous Na2S04, filtered and concentrated. The resulting residue was dissolved in EtOAc, petroleum ether was added with vigorous stirring, then filtrated to give 20d as a white solid (8 g, yield: 47%). |
47% | Stage #1: methyl 2-(benzyloxycarbonylamino)-2-methoxyacetate With phosphorus tribromide In toluene at 70℃; for 20h; Stage #2: triethyl phosphate In toluene at 70℃; for 2h; | 20.20-3 Methyl 2-(benzyloxycarbonylamino)-2-(diethoxyphosphoryl)acetate To a solution of 20c (12 g, 47.4 mmol) in toluene (60 mL) was added PBr3 (12.8 g, 47.4 mmol) at 70 °C, the reaction was stirred at 70 °C for 20 h, then triethyl phosphate (7.87 g, 47.4 mmol) was added dropwise and stirred at 70 °C for another 2 h. The mixture was concentrated, diluted with EtOAc, and washed with sat. NaHC03 aq.. The organic layers were dried over anhydrous Na2S04, filtered and concentrated. The resulting residue was dissolved in EtOAc, petroleum ether was added with vigorous stirring, then filtrated to give 20d as a white solid (8 g, yield: 47%). |
47% | Stage #1: methyl 2-(benzyloxycarbonylamino)-2-methoxyacetate With phosphorus tribromide In toluene at 70℃; for 20h; Stage #2: triethyl phosphate In toluene at 70℃; for 2h; | 3 Step 3: Methyl 2-(benzyloxycarbonylamino)-2-(diethoxyphosphoryl)acetate [231] To a solution of methyl 2-(((benzyloxy)carbonyl)amino)-2-methoxyacetate (12 g, 47.4 mmol) in toluene (60 mL) was added PBr3 (12.8 g, 47.4 mmol) at 70 00 the reaction was stirred at 70 00 for 20 h, then triethyl phosphate (7.87 g, 47.4 mmol) was added dropwise and stirred at 70 00 for another 2 h. The mixture was concentrated, diluted withEtOAc, and washed with sat. NaH 003 aq.. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was dissolved in EtOAc, petroleum ether was added with vigorous stirring, then filtrated to afford the title compound as a white solid (8 g). Yield: 47%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | With 15-crown-5 In o-xylene at 105℃; for 14h; | 1-5 Example 3 According to the proportion of raw materials, o-xylene is 10ml(based on a total mass of 1 g of ethyl fluorobromide and triethyl phosphite),The amount of 15-crown (ether)-5 is 0.20% by weight based on the mass of ethyl fluorobromoacetate.The molar ratio of ethyl fluorobromoacetate to triethyl phosphite was 1:1.05. In a dry three-necked flask equipped with a stirring device, a reflux device, and a thermometer, mesitylene, ethyl fluorobromide, triethyl phosphite, and 15-crown (ether)-5 were successively introduced, and the stirring device was turned on. The temperature was adjusted to 105 ° C under reflux for 14 h. It was monitored by TLC plate and GC-MS. After the reaction was completed, it was naturally cooled, and the low-boiling substance was evaporated under reduced pressure to obtain a yellow transparent liquid. The spur fractionation column oil pump was distilled under reduced pressure, and the temperature was collected at a temperature of 90-120 ° C / 16 mm. It is triethyl 2-fluorophosphorylacetate. The total yield in this example was tested to be 96.4%. |
92% | at 130℃; for 24h; | 31 Preparation of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (473-1) A mixture of ethyl 2-bromo-2-fluoroacetate (2.5 g, 13.5 mmol) and triethyl phosphate (5.8 mL, 32.8 mmol) was heated at 130°C for 24 hr. The excess of triethyl phosphate was removed by distillation under reduced pressure to afford ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (473-1) (3.0 g, 92% yield) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | at 180℃; for 8h; | The 9,10-Bis(bromomethyl)anthracene (1.2 g, 3.3 mmol) was mixed with triethyl phosphate (10 mL). Resulting mixture was refluxed at 180C for 8 h in order to obtain the pure product. The solvent was then removed at vacuum and the residue product was purified by a column chromatography on silica gel using ethyl acetate/CH2Cl2 as the eluent. Yield: 1.05 g (68%). 1H NMR (300 MHz, CDCl3): delta 8.38 (m, 4H), delta 7.6 (m, 4H), 4.25 (d, 4H), 3.8 (m, 8H), 1.06 ppm (t, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.5% | Stage #1: triethyl phosphate With diethylamine at 125℃; for 30h; Stage #2: 1,2,3,4-tetramethylimidazolium methyl carbonate In methanol | 1 Synthesis of 1,2,3,4-tetramethylimidazolinium diethylphosphate (K-1) In a pressure-resistant container equipped with a stirrer,162 parts (0.89 mol) of triethyl phosphate (manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) (A-1)130 parts (1.78 mol) of diethylamine (manufactured by BASF) (B-1) were charged, and the temperature was raised to 125 ° C. The reaction was allowed to continue for 30 hours with stirring. After cooling, the P-NMR of the reaction solution was measured. As a result, the peak of triethyl phosphate disappeared and only the peak of diethyl phosphate appeared. 260 parts (0.9 mol) of a methanol solution of 1,2,3,4-tetramethylimidazolium methyl carbonate (J-1) was added to this reaction solution for salt exchange. This solution was concentrated under reduced pressure at 100 ° C. using a rotary evaporator to obtain a yellow-brown solid. It was confirmed by 1 H-NMR and P-NMR that this yellowish brown solid was 1,2,3,4-tetramethylimidazolium diethylphosphate (K-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.1% | With a stirrer,A distillation apparatus, a thermometer, and a gas pipe,0.100 mol of trimethylol ethane was added,0.200 mol of dipentaerythritol,0.55 mol of triethyl phosphite,0.002 mol of polyphosphoric acid,Heating and nitrogen,Slowly heated to 85 C,The reaction was carried out at this temperature for 5 h to give the intermediate and ethanol, and ethanol was distilled off. Then 0.350mol of triethyl phosphate, 0.008mol bromo isobutane added to the intermediate, at 185 C for 16h, decompression and extraction of excess triethyl phosphate (apply), in a colorless transparent viscous liquid 126.275 G, yield 96.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.5% | With trichlorophosphate; at -5 - -1℃; for 15h; | <strong>[146-78-1]Fludarabine</strong> (10g), triethyl phosphate (90mL), phosphorus oxychloride (6mL) were placed under stirring -5~-10C low temperature circulating pump, while maintaining the internal temperature -5 ~ -1 C; stirring reaction at -5 ~ -1 C for 15 hours; when the amount of fludarabine in the HPLC detection area, less than 2% is considered The reaction was completed, then pure water (50 mL) was added to the obtained mixture under stirring, and washed with dichloromethane. The obtained aqueous phase was adjusted to pH=3 with 50% NaOH solution, concentrated under reduced pressure at 35-40 C, and recrystallized. Filtration, the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was dried under vacuum at 45-50 C for 10-12 hours to obtain a crude product of fludarabine phosphate having a purity of 99.2% and a yield of 73.3%.The crude fludarabine phosphate obtained by the above preparation method is added to 100 mL of pure water at room temperature, stirred uniformly, and 50% NaOH solution is slowly added dropwise until completely dissolved, and the filtrate is added dropwise to a dilute hydrochloric acid solution at room temperature with a white solid. Precipitate,After suction filtration, the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was vacuum-dried at 45-50 C for 10-12 hours to obtain fludarabine phosphate. The purity was 99.9%, and the yield was 96.5. %. |
81.02% | To a 500 mL flask was added 20 g of fludarabine followed by 200 mL of triethyl phosphate, and the flask was placed at a low temperature of -6 CReaction bath, 20min after slowly dropping phosphorus oxychloride 20mL (side drop while stirring), the reaction 12 hours (TCL tracking). Reaction reachedTo the request after the flask quickly add 80mL water and 200mL dichloroethane, standing for 30 minutes after the extraction of water and organic phase, the waterAdjust the pH value to 2-3. Recrystallization white floc with a Buchner funnel filter, vacuum dry weighing a white powder20.71 g, yield 81.02%, HPLC mass fraction 99.95%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: triethyl phosphate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.666667h; Inert atmosphere; Stage #2: acetophenone In tetrahydrofuran for 10.1667h; Reflux; Inert atmosphere; | GP-1: Horner-Wadsworth-Emmons reaction. General procedure: In a flame-dried 200 mL three-necked flask in a nitrogen atmosphere, sodium hydride (60 % dispersion in oil) was washed with hexane and suspended in THF. Triethylphosphonoacetate was dropped to the suspension at 0 °C over 10 min and stirred at r.t. for 30 min. After that, a solution of the ketone in THF was added in 10 min and the reaction mixture heated to reflux for 10 h. After cooling to r.t., an aqueous NH4Cl soluion was added and extracted with 4x diethyl ether. The organic phases were washed wit hbrine and dried over Na2SO4. After solvent evaporation, the product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: triethyl phosphate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.666667h; Inert atmosphere; Stage #2: 1-(4-methoxyphenyl)ethanone In tetrahydrofuran for 10.1667h; Reflux; Inert atmosphere; | GP-1: Horner-Wadsworth-Emmons reaction. General procedure: In a flame-dried 200 mL three-necked flask in a nitrogen atmosphere, sodium hydride (60 % dispersion in oil) was washed with hexane and suspended in THF. Triethylphosphonoacetate was dropped to the suspension at 0 °C over 10 min and stirred at r.t. for 30 min. After that, a solution of the ketone in THF was added in 10 min and the reaction mixture heated to reflux for 10 h. After cooling to r.t., an aqueous NH4Cl soluion was added and extracted with 4x diethyl ether. The organic phases were washed wit hbrine and dried over Na2SO4. After solvent evaporation, the product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: triethyl phosphate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.666667h; Inert atmosphere; Stage #2: methyl 2-naphthyl ketone In tetrahydrofuran for 10.1667h; Reflux; Inert atmosphere; | GP-1: Horner-Wadsworth-Emmons reaction. General procedure: In a flame-dried 200 mL three-necked flask in a nitrogen atmosphere, sodium hydride (60 % dispersion in oil) was washed with hexane and suspended in THF. Triethylphosphonoacetate was dropped to the suspension at 0 °C over 10 min and stirred at r.t. for 30 min. After that, a solution of the ketone in THF was added in 10 min and the reaction mixture heated to reflux for 10 h. After cooling to r.t., an aqueous NH4Cl soluion was added and extracted with 4x diethyl ether. The organic phases were washed wit hbrine and dried over Na2SO4. After solvent evaporation, the product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.8% | With iodine In methanol at 20℃; for 12h; | 1.1 1) Synthesis of intermediate N, N-dipropylaminebenzyl diethyl phosphite In 50mL round bottom flask, 0.291g (1mmol) of 4-(N,N-dipropylamino)benzylalcohol , triethylphosphate was dissolved in methanol 5mL, and then the mixed solution was added dropwise 0.258g (1mmol) of elemental iodine at rt 12h.Extracted with dichloromethane, dried, and concentrated dichloromethane as eluent to separation by column chromatography.To obtain the product 0.32g, yield (Yield): 77.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: triethyl phosphate; (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(6-((2-(methylthio)ethyl)amino)-2-((3,3,3-trifluoropropyl)thio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; trichlorophosphate at 0℃; for 0.5h; Stage #2: clodronic acid mono n-butylamine With tributyl-amine In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Stage #3: With sodium hydrogencarbonate In water | 23 Example 23: Preparation of the compound of formula (I) by Cangrero At room temperature,20.8 g (42.8 mmol) of the compound of the formula (II) and 27.5 g (128.4 mmol) of 1,8-bisdimethylaminonaphthalene were added to 400 mL of triethyl phosphate,System dissolved after cooling to 0 ,32.7 g (214 mmol) of phosphorus oxychloride was added dropwise to the system,The dropping rate was 6 mL / min. The reaction solution gradually changed to a white suspension,After dripping,0 incubation reaction 0.5h,And then the chlorine ringPhosphoric acid mono-n-butylamine salt(428 mmol) and tri-n-butylamine (78.5 g, 428 mmol) were dissolved in 450 mL of anhydrous N, N-dimethylformamide,And added dropwise to the reaction system at 0 ° C,The dropping rate was 6 mL / min,In the process of dropping,The system gradually become clear,Drop finished,Rose to room temperature reaction 2h,TLC monitoring of raw materials is completed,Stop the reaction,Add 500mL concentration of 0.5mol / L ammonium bicarbonate aqueous solution,Extracted twice with ethyl acetate,The resulting aqueous phase was purified by DEAE-SEPHADEX A25 ion exchange column (0-1 mol / L aqueous ammonium bicarbonate solution as eluent)After the eluent containing the pure product was frozen,Placed in a vacuum freeze dryer dry,24.6 g of a white powder,I.e., the form of the compound of formula (I)Yield 68%.The above-mentioned pure compound (I) ammonium salt was dissolved in 200 mL of purified water containing 2.45 g of sodium bicarbonate,After stirring for 10 min,Placed in a vacuum freeze dryer dry,To obtain 20 g of a white powder,I.e. the form of the sodium salt of the compound of formula (I)That is, Cangerello. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.7% | In methanol at 80℃; for 48h; | 4 Example four Weigh 0.1 mol of monomethyl carbonate N-picoline salt and 80 g of methanol solvent into a solution; Weigh triethyl phosphate 0.12 mol, add it to the solution, at 80 °C ~ 150 ° C. The pressure was maintained at 0-2 MPa for 36 hours. Specifically, this example was maintained at 80° C. and 2 MPa for 48 hours; the reaction was completed to obtain a methanol solution of diethyl phosphate N-methylpyridinium salt. The reaction completed solution was heated to a degree of reduced pressure of 1.0 kPa or less and 50° C. After the methanol was distilled off, the temperature was increased from 50° C. to 100° C. and heated for 5 hours to produce monomethyl carbonate and ethyl carbonate. Distillation of esters, methanol, and carbon dioxide, etc., in which methanol and carbon dioxide are produced by the thermal decomposition of monomethyl carbonate, in a very small amount. After distillative separation was completed, the dihydrocarbyl phosphate ester salt of the present example, diethyl phosphate N-picoline salt, was obtained. The yield of the dihydrocarbyl phosphate salt in this example was 98.7%, the water content was 0.09%, the pH of the 1:100 aqueous solution was 6.65, the main content was 99.4% by cation chromatography, and the main content was 99.6% by anion chromatography. It can be seen that the preparation method of the present example has simple reaction conditions and is easy to operate. The dihydrogen phosphate ester salt prepared has almost no moisture, and water, halogen elements and other impurities are not introduced during the reaction, and the cation structure does not change before and after the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.7% | In methanol at 130℃; for 36h; | 5 Example 5 Weigh 0.1 mol of monomethyl carbonate N-methylpyrrolium salt and mix it with 80 g of methanol solvent; Weigh 0.12 mol of triethyl phosphate and add it to the solution at 80°C150° C. The pressure was maintained at 0-2 MPa for 36 hours. Specifically, this example was maintained at 130° C. and 1 MPa for 36 hours. The reaction was completed to obtain a methanol solution of diethyl phosphate N-methylpyrrole salt. The reaction completed solution was heated at a pressure of 1.0 kPa or less and at 50°C. After methanol was distilled off, the temperature was increased from 50°C to 100°C, and the mixture was heated for 2 hours to produce monomethyl carbonate and ethyl carbonate. Distillation of esters, methanol, and carbon dioxide, etc., in which methanol and carbon dioxide are produced by the thermal decomposition of monomethyl carbonate, in a very small amount. After completion of the distillation separation, the dihydrocarbyl phosphate ester salt of the present example, diethyl phosphate N-methylpyrrolide salt, was obtained. The yield of the dihydrocarbyl phosphate ester in this example was 98.7%, the moisture content was 0.08%, the pH value of the 1:100 aqueous solution was 6.65, the main content was 99.5% by cation chromatography, and the main content was 99.6% by anion chromatography. It can be seen that the preparation method of the present example has simple reaction conditions and is easy to operate. The dihydrogen phosphate ester salt prepared has almost no moisture, and water, halogen elements and other impurities are not introduced during the reaction, and the cation structure does not change before and after the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In methanol at 120℃; for 36h; | 1 example 1 Weigh 0.1 mol of 1,2,3,4-tetramethylimidazolinium•methyl carbonate salt and mix it with 60 g of methanol solvent; Weighed 0.15mol of triethyl phosphate, it was added to the solution, maintain temperatureat 80 °C ~ 150 °C, pressure 0 ~ 2MPa for 36 hours, in this case specifically at 120 °C, 1MPa and maintained for 36 hours; Upon completion of the reaction, 1,2,3,4-tetramethylimidazolinium * diethyl phosphonate anion in a methanol solution was obtained. The reaction completed solution was heated to a degree of reduced pressure of 1.0 kPa or less at 50° C. After the methanol was distilled off, the temperature was raised from 50° C. to 100° C and heated for 2 hours. Distillation separation of monomethyl carbonate, ethyl methyl carbonate, methanol, carbon dioxide, etc. Wherein, methanol and carbon dioxide are produced by the thermal decomposition of monomethyl carbonate, and the amount was very small. After distillative separation was completed, the obtained phosphate dialkyl ester salt of this example, namely, 1,2,3,4-tetramethylimidazolinium• diethyl phosphate salt is obtained. The yield of the phosphate dialkyl ester salt in this example was 99.0%, the moisture content was 0.08%, the pH value of the 1:100 aqueous solution was 6.70,the main content of cation chromatography was 99.6% and the main content of anion chromatography was 99.7%. It can be seen that the preparation method of the present example has simple conditions and is easy to operate. The prepared dialkyl phosphate ester salt has almost no moisture, and water or halogen elements are not introduced during the entire reaction, and the cation structure does not change before and after the reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; toluene Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.66% | Stage #1: methoxybenzene With N,N,N,N,N,N-hexamethylphosphoric triamide; n-butyllithium In tetrahydrofuran at 0 - 50℃; Stage #2: triethyl phosphate In tetrahydrofuran at -10 - 50℃; | 1.1; 2.1; 3.1; 4.1 (1) Preparation of bis (2-methoxyphenyl) phosphonate Under anhydrous and anaerobic conditions, 6.48 g of anisole and 10.75 g of hexamethylphosphoryl triamine were added to 32.4 mL of dry tetrahydrofuran (solvent I), the temperature was lowered to -0 ° C, and 39.38 mL of 1.6 mol was added dropwise at a controlled temperature. / L of n-BuLi solution. After the dropwise addition, the temperature was stirred for 1 to 2 hours, and the temperature was raised to 20 to 50 ° C. After the reaction was tracked and detected, the temperature was lowered to -10 ° C and the temperature-controlled dropwise addition of triethyl phosphate was 5.46. g. After the dropwise addition, the reaction is held for 1 to 2 hours and then heated to 50 ° C. After the tracking reaction is completed, the temperature is lowered to room temperature. The reaction solution is slowly dropped into the ice water containing 10% sulfuric acid under stirring, and the solution is separated and washed. Tetrahydrofuran was recovered under reduced pressure, a large amount of solid was precipitated, and dried to obtain 8.92 g of white bis (2-methoxyphenyl) phosphonic acid ethyl ester with a purity of 98.45% and a yield of 95.66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: para-diiodobenzene With nickel dichloride In 1,3,5-trimethyl-benzene at 160℃; for 1h; Inert atmosphere; Stage #2: triethyl phosphate In 1,3,5-trimethyl-benzene at 160℃; for 4h; | 3.2.1 Synthesis of diethyl 4-iodophenylphosphonate In a two necked 50mL flask 3.0 g (0.009mol) of 1,4-diiodobenzeneand 0.059 g (0.0004 mol) of anhydrousNiCl2 were suspended in 10mL of mesitylene. The suspensionwas placed under nitrogen and heated to 160°Cwith refluxing. After 1 h 1.74 g (0.01 mol) of triethylphosphite was added dropwise over 2 h. After refluxingfor another 2 h for completion of the reaction, theyellow suspension was allowed to cool to the room temperature.The yellow mixture was filtered to remove therest of nickel salt, washed with hexane and heated to130°C to remove mesitylene. The excess of solvent wasremoved under reduce pressure. The yellow residue wassubjected to column chromatography (silica gel, 1:1 ethylacetate:hexane). The resulting liquid was dried underreduce pressure to afford 1.83 g (61%) of pure product.- 1H NMR (300MHz, CDCl3): δ (ppm)=1.31 (t, 6H), 4.11(q, 4 H), 7.51 (d, 2H), 7.82 (d, 2H) (Fig. S1). - 13C NMR(300MHz, DMSO-d6): δ (ppm)=16.94 (CH3), 62.88 (CH2),127.38 (O-CH3), 129.9 (O-CH3), 133.80-138.39 (aromatic C atoms) (Fig. S2). - 31P{H} NMR (300MHz, DMSO-d6): δ (ppm)=18.05 (Fig. S3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With sodium dithionite; tetrabutylammomium bromide; N-ethyl-N,N-diisopropylamine; zinc(II) chloride In water; N,N-dimethyl-formamide; acetonitrile at 120℃; for 15h; Inert atmosphere; Schlenk technique; | |
70% | With sodium dithionite; tetrabutylammomium bromide; triethylamine In N,N-dimethyl acetamide; water at 120℃; for 15h; Inert atmosphere; | 36 Synthesis of compound 3aj: Add the redox ester derived from 1-phenylcyclopentane carboxylic acid (67.1 mg, 0.2 mmol), sodium dithionite (69.6 mg, 0.4 mmol) to the reaction tube,Triethyl phosphate (109.3mg, 0.6mmol), triethylamine (40.5mg, 0.4mmol),Tetrabutylammonium bromide (96.7mg, 0.3mmol), water (70μL), DMA (2mL),Under the protection of nitrogen, react at 120°C for 15 hours, and monitor the redox ester to be consumed completely.Move to room temperature, quench with water, extract with ethyl acetate, and collect the organic phase.The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure.The product 3aj (33.3mg) was separated by column chromatography with a yield of 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.07% | With sodium carbonate at 78 - 200℃; | 1.2; 2; 3 Preparation method Feed 313.9g of tris(2-hydroxyethyl) isocyanurate (THEIC) and 436.1g of triethyl phosphate (TEP) (the molar ratio of the two is 1:2) to a clean and dry capacity In a 1L three-necked flask, 6g of anhydrous sodium carbonate was added as a catalyst.(2) Keep the inside and outside of the three-necked flask dry, put it in a digital temperature-controlled oil bath, connect to the condenser, insert a thermometer and a stirring rod, continue to stir with a timing electric stirrer, and slowly heat up until there is distillate (ethanol ) Distillation, the process of distilling the distillate keeps the temperature of the distillation head thermometer at about 78°C.(3) The reaction system in the three-necked flask was slowly heated to 200°C.(4) Until the amount of distilled substances approaches or reaches the theoretical amount of alcohol (according to the reaction equation, 1 mol THEIC can produce 3 mol of ethanol), cool down to 120°C, and distill under reduced pressure (-0.01MPa) at 120°C until nothing After any fraction is distilled off, the reaction is closed (the heating is stopped), and the material is discharged after being cooled to room temperature to obtain 506 g of a light yellow viscous liquid.The yield was 98.07%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.5% | With pyridinium perchlorate In chloroform at 0 - 20℃; | 4.1.5. Synthesis of (5,6-Dimethoxyisobenzofuran-1(3H)-one-3-yl)phosphonic acid diethylester (7) Compound 6 (2.5 g, 11 mmol) and triethyl phosphate (3.65 g, 22mmol) were dissolved in CHCl3 (30 mL), and then PyHClO4 was addedat 0 C. The resulting mixture stirred at room temperature overnight.After that, to the reaction mixture dichloromethane (30 mL) was added,washed with H2O (4 × 20 mL) and brine (2 × 20 mL), dried over sodiumsulfate and filtered, concentrated under reduced pressure. The obtainedresidue was recrystallized from ether to afford the desired compound 7as a light yellow solid; yield 80.5%; mp 120.1 ~ 122.3 C; 1H NMR (600MHz, CDCl3) δ 7.32 (s, 1H) , 7.18 (s, 1H), 5.59 (d, J = 10.8 Hz, 1H),4.34-4.29 (m, 2H), 4.04-4.02 (m, 1H), 4.00 (s, 3H), 3.96 (s, 3H),3.88-3.83 (m, 1H), 1.43 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydride In 1-methyl-pyrrolidin-2-one at 120℃; for 24h; | Compounds 8a-8j and 9a-9d; General Procedure General procedure: All reactions were carried out on 0.5-mmol scale. A reaction tube wascharged with NaH (3.0 equiv), carbonyl compound (1.0 equiv) andNMP (3 mL) were added followed by addition of trialkyl phosphate(3.0 equiv). Then, this reaction mixture was heated to 120 °C for 24 h.After that, the reaction mixture was diluted with Et2O, washed withwater and extracted with Et2O. The organic layer was dried overNa2SO4 and concentrated to obtain crude product which was purifiedby column chromatography (EtOAc/hexane) to afford the desiredproduct 8 and 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With lithium diisopropyl amide In tetrahydrofuran at 0 - 75℃; for 24h; | Compounds 13a-13h and 14a-14j; General Procedure General procedure: All reactions were carried out on 0.5-mmol scale. A reaction tube wascharged with N,N-disubstituted amide (1.0 equiv), THF (3 mL) wasadded and the tube cooled to 0 °C. Then, LDA (1.5 equiv) was addedand stirring continued for 15 min at 0 °C followed by addition of trialkylphosphate (1.5 equiv). Then, this reaction mixture was heated to75 °C for 24 h. After that, the reaction was quenched with NH4Cl andthe mixture extracted with EtOAc. The organic layer was dried overNa2SO4 and concentrated to obtain crude product which was purifiedby column chromatography (EtOAc/hexane) to afford the desiredproduct 13 and 14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With lithium diisopropyl amide In tetrahydrofuran at 0 - 75℃; for 24h; regioselective reaction; | Compounds 5a-5n and 6a-6l; General Procedure General procedure: All reactions were carried out on 0.5-mmol scale. A reaction tube wascharged with amide (1.0 equiv), THF (3 mL) was added and the tubecooled to 0 °C. Then, LDA (1.5 equiv) was added and stirring continued for 15 min at 0 °C followed by addition of trialkyl phosphate (1.5equiv). Then, this reaction mixture was heated to the required temperaturefor 24 h. After that, the reaction was quenched with NH4Cland the mixture extracted with EtOAc. The organic layer was driedover Na2SO4 and concentrated to obtain crude product which was purifiedby column chromatography (EtOAc/hexane) to afford the desiredproduct 5 and 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.5% | With tetrabutylammomium bromide In n-heptane at 120℃; for 20h; Autoclave; Sealed tube; | 1-6 Example 4: Synthesis of Triethyl Phosphate Experimental operation: 97 g of sodium diethyl phosphate obtained from wastewater treatment was added to a 1000 mL autoclave. Add 112 g of cold ethyl chloride into 350 mL of cold heptane to form a mixture of heptane and ethyl chloride. Add 9.3g of tetrabutylammonium bromide and heptane chloroethane mixture to the autoclave in turn. The autoclave was sealed, stirred and heated to 120°C for 20 hours. After the reaction, the autoclave was turned off and heated, and the temperature was naturally cooled to 50° C. under stirring, the reaction system was separated by filtration, and the filter cake was washed 3 times with 70 mL of heptane. Combine all the heptane solutions obtained in the above process into a 500 mL single-neck round bottom flask, concentrate under reduced pressure to obtain crude triethyl phosphate, and distill the crude product under reduced pressure to obtain 83 g of the target product triethyl phosphate with a purity of 95.5%. The rate is 79.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: ethanol With phosphorous pentoxide at 26℃; for 2h; Green chemistry; Stage #2: ethanol With 1-n-butyl-3-methylimidazolium tetrafluoroborate at 175℃; for 4.5h; Microwave irradiation; Green chemistry; Stage #3: ethyl iodide With triethylamine In toluene at 135℃; for 4h; Microwave irradiation; Green chemistry; | Alkylating Esterification of the Mixture of Di- and Trialkylphosphates (2a/3a, 2b/3b, 2c/3c and 2d/3d); General procedure: The crude mixtures of dialkylphosphate ((RO)2P(O)OH, 2) (ca. 93%) and trialkylphosphate ((RO)3P(O), 3) (ca. 7%) (R = Bu: ca. 3.4 mmol, R = Pent: ca. 3.1 mmol, R = Pr: ca. 3.7 mmol, R = Et: ca. 4.0 mmol) were esterified further. To the mixture of esters 2 and 3 in toluene (1 mL) was added the corresponding alkyl bromide (1 equiv, BuBr: 0.35 mL, PentBr: 0.36 mL, PrBr: 0.31 mL, EtI: 0.32 mL) and triethylamine (1.1 equivalents, 0.49 mL, 0.44 mL, 0.52 mL and 0.61 mL, respectively). The vial containing the components was irradiated in the MW reactor at 135 °C for 2-4 h with stirring. The crude mixtures obtained after filtration and evaporation were purified by column chromatography using a silica gel layer of 20 cm and ethyl acetate as the eluent to afford the corresponding trialkylphosphates (3a-d) as colourless oils. |
Tags: 78-40-0 synthesis path| 78-40-0 SDS| 78-40-0 COA| 78-40-0 purity| 78-40-0 application| 78-40-0 NMR| 78-40-0 COA| 78-40-0 structure
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P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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