* 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.
Example 2 330 9 (7.17 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 18 g (1.06 mol) of ammonia gas are then introduced at this temperature. 200 g (0.907 mol) of chloro(diphenyl)phosphine are then added dropwise at this temperature in one hour. The mixture is then allowed to come to room temperature with stirring and is stirred for a further 3.5 hours. The mixture is then cooled, filtered by suction and washed with ethanol. The filtrate is freed from ethanol and any ammonia present in vacuo. The remaining residue is freed from a slight precipitate by filtration through a glass frit. 172 g of ethyl diphenylphosphinite are then obtained by thin film distillation at a bath temperature of 140° C. and 0.3 mbar. This corresponds to a yield of 83percent of theory.
82%
With ammonia In ethanol
Example 1 330 g (7.17 mol) of absolute ethanol are cooled to -15° C. under a nitrogen atmosphere. 26.5 g (1.56 mol) of ammonia gas are introduced thereto at this temperature with constant stirring. 200 g (0.907 mol) of chloro(diphenyl)-phosphine are then added dropwise at this temperature. The mixture is then allowed to come to room temperature with stirring and is then kept under reflux for 11 hours until virtually no more ammonia gas escapes. The mixture is then cooled, filtered by suction, washed with ethanol and dried. 48 g of crude ammonium chloride are obtained. The filtrate is freed from ethanol and any ammonia present in vacuo. The remaining residue is freed from a slight salt precipitate by filtration through a glass frit. 170 g of ethyl diphenylphosphinite are then obtained by thin film distillation at a bath temperature of 160° to 175° C. and a pressure of 0.5 mbar. This corresponds to a yield of 82percent of theory.
88%
With pyridine In ethanol
EXAMPLE 2 Preparation of Ethyl Diphenylphosphinite A solution of diphenylphosphinous chloride (135 mmol) in dry ether (120 mL) was treated dropwise at 5° C. with a solution of ethanol (200 mmol) and pyridine (134 mmol) in ether (120 mL). After addition was complete, the mixture was warmed to room temperature, filtered under argon, and the solid hydrochloride washed with ether. Evaporation of the solvent gave an oil which was purified by Kugelrohr distillation at 95° C. (0.1 mmHg). Yield: 119 mmol (88percent); 1 H NMR (CDCl3) δ7.6-7.2 (m, 10H), 3.95 (doublet of quartets, JH-H =7 Hz, JP-H =10 Hz, 2H), 1.30 (t, J=7 Hz, 3H).
Reference：
[1] Patent: US5705669, 1998, A,
[2] Patent: US5705669, 1998, A,
[3] Patent: US5705669, 1998, A,
[4] Patent: US5705669, 1998, A,
[5] J. Gen. Chem. USSR (Engl. Transl.), 1961, vol. 31, p. 2214 - 2217[6] Zhurnal Obshchei Khimii, 1961, vol. 31, p. 2377 - 2380
[7] Patent: US4574060, 1986, A,
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[1] Organic Letters, 2018, vol. 20, # 11, p. 3286 - 3290
[2] Inorganic Chemistry, 2018, vol. 57, # 18, p. 11530 - 11536
[3] Zhurnal Obshchei Khimii, 1950, vol. 20, p. 107,112;engl.Ausg.S.113,118
[4] Doklady Akademii Nauk SSSR, 1949, vol. 66, p. 389,391[5] Chem.Abstr., 1950, p. 127
[6] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1967, p. 568 - 572[7] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1967, p. 591 - 595
[8] Journal of Organic Chemistry, 1961, vol. 26, p. 4623 - 4626
[9] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1972, p. 304 - 311
[10] Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 2-3, p. 383 - 388
[11] Chemical Communications, 2015, vol. 51, # 92, p. 16561 - 16564
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[1] Synthesis, 2011, # 15, p. 2490 - 2494
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[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1910, vol. 42, p. 404,411[2] Chem. Zentralbl., 1910, vol. 81, # II, p. 454
[3] Chemische Berichte, 1968, vol. 101, # 4, p. 1414 - 1427
[4] Canadian Journal of Chemistry, 2001, vol. 79, # 5-6, p. 752 - 759
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[1] J. Gen. Chem. USSR (Engl. Transl.), 1961, vol. 31, p. 2692 - 2695[2] Zhurnal Obshchei Khimii, 1961, vol. 31, # 9, p. 2889 - 2894
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[1] Justus Liebigs Annalen der Chemie, 1968, vol. 712, p. 21 - 27
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[1] Justus Liebigs Annalen der Chemie, 1968, vol. 712, p. 21 - 27
8
[ 64-17-5 ]
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[ 719-80-2 ]
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[1] J. Gen. Chem. USSR (Engl. Transl.), 1961, vol. 31, p. 2214 - 2217[2] Zhurnal Obshchei Khimii, 1961, vol. 31, p. 2377 - 2380
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[1] Phosphorus and Sulfur and the Related Elements, 1983, vol. 17, p. 283 - 296
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[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1910, vol. 42, p. 404,411[2] Chem. Zentralbl., 1910, vol. 81, # II, p. 454
Ethyl diphenyl phosphinite (12.6 g, 55 MMOL) is added, at 60°C and under argon, to a solution of the compound of formula (37) (15.2 g, 36.6 MMOL) IN toluene (370 ml). The reaction mixture is stirred at 60°C for 3 hours and then concentrated. The residue is dissolved in 10 ml of toluene, and 10 ml of hexane are added, the product precipitating out in the form of a colourless powder, which is filtered off. In that manner, 14.3 G (73 percent) of the phosphine oxide (38) can be obtained. aH NMR (300 MHz, CDCI3) : 1.22 (d, J = 6.7 Hz, 6H); 3.32-3. 45 (m, 1H); 3.41 (s, 3H); 3.47 (s, 3H); 3.89 (d, J = 12.9 Hz, 2H); 6.86 (dd, J = 8.7, 8.7 Hz, 2H); 7.09 (dd, J = 8.6, 5.3 Hz, 2H); 7.27-7. 45 (m, 10H). 13C NMR (75 MHz, CDCI3) : 22.1, 30.0 (JCP = 64.8 Hz), 33.1, 33.5, 42.7, 114.1 (Jcp = 8.2 Hz), 115.5 (JCF = 21.7 Hz), 128.8 (Jcp = 11. 8 Hz), 130.9 (Jcp = 9.3 Hz), 132.1 (JCF = 8.4 Hz), 132.1 (Jcp = 2.9 Hz), 133.3, 134.7 (Jcp = 2.3 Hz), 157.3 (Jcp = 2.3 Hz), 162.9 (JCF = 249 Hz), 166.3 (Jcp = 4.6 Hz). 3'P NMR (121 MHz, CD13) : 27.7.
73%
at 90 - 100℃; for 9 h;
Preparation 5. [190] Diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide [191] N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (10.0 g), toluene (100.0 mL), and diphenyl(ethoxy)phosphorane (6.2 g) were added to a reactor. The reaction mixture was stirred at 90.similar.100°C for 9 hours and then water (80.0 mL) was added thereto. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane =1:1) to obtain diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide as a white solid (9.4 g, yield 73percent).[192] 1H-NMR, 400 MHz, CDCl3, ppm : 1.26(d, 6H), 3.41(m, 1H), 3.46(s, 3H), 3.51(s, 3H), 3.92(d, 2H), 6.95(m, 2H), 7.12(t, 2H), 7.57(m, 12H)
With trifluorormethanesulfonic acid; at 100℃; for 16h;Inert atmosphere;
To 0.1 mol of ethoxydiphenylphosphine, 2 mmol of trifluoromethanesulfonic acid as a catalyst was added, and under a nitrogen atmosphere,The reaction was carried out at 100 C. for 16 hours, and 31 P-NMR of the obtained product was measured. The reaction selectivity of ethyldiphenylphosphine oxide was 80%. Ethyldiphenylphosphine oxide was separated from the obtained product by liquid chromatography and 1H-NMR, 13C-NMR and 31P-NMR were measured, and the NMR charts shown in FIGS. 19, 20 and 21 were obtained.
With water; Selectfluor; In acetonitrile; at 20℃; for 0.166667h;
General procedure: To a solution of 1 (0.2 mmol) in 2 mL of CH3CN/H2O(v/v = 100/1) was added Selectfluor (71 mg, 0.2 mmol). The mixture was stirred at room temperature for 5-60minutes. After removal of the solvent, the residue was then purified by flash column chromatography on silica gel with petroleum ether/ethyl acetate to give the desired product 2.
Example 1Diphenyl(phthalimidomethyl)phosphine oxide IVToluene (25 ml) was added to a mixture of ethyl diphenylphosphinite (5 g, 21.71 mmole) and the N-(bromomethy)phthalimide III (5.21 g, 21.70 mmole) at room temperature.The reaction mixture was heated to 90° C. and maintained at this temperature for 48 h when the reaction was complete as indicated from the TLC of the reaction mixture.The reaction mixture was concentrated under reduced pressure, triturated with toluene and filtered to furnish the phosphine oxide compound IV as a solid; yield: 6 g, 76.5percent.
Ethyl diphenyl phosphinite (12.6 g, 55 MMOL) is added, at 60C and under argon, to a solution of the compound of formula (37) (15.2 g, 36.6 MMOL) IN toluene (370 ml). The reaction mixture is stirred at 60C for 3 hours and then concentrated. The residue is dissolved in 10 ml of toluene, and 10 ml of hexane are added, the product precipitating out in the form of a colourless powder, which is filtered off. In that manner, 14.3 G (73 %) of the phosphine oxide (38) can be obtained. aH NMR (300 MHz, CDCI3) : 1.22 (d, J = 6.7 Hz, 6H); 3.32-3. 45 (m, 1H); 3.41 (s, 3H); 3.47 (s, 3H); 3.89 (d, J = 12.9 Hz, 2H); 6.86 (dd, J = 8.7, 8.7 Hz, 2H); 7.09 (dd, J = 8.6, 5.3 Hz, 2H); 7.27-7. 45 (m, 10H). 13C NMR (75 MHz, CDCI3) : 22.1, 30.0 (JCP = 64.8 Hz), 33.1, 33.5, 42.7, 114.1 (Jcp = 8.2 Hz), 115.5 (JCF = 21.7 Hz), 128.8 (Jcp = 11. 8 Hz), 130.9 (Jcp = 9.3 Hz), 132.1 (JCF = 8.4 Hz), 132.1 (Jcp = 2.9 Hz), 133.3, 134.7 (Jcp = 2.3 Hz), 157.3 (Jcp = 2.3 Hz), 162.9 (JCF = 249 Hz), 166.3 (Jcp = 4.6 Hz). 3'P NMR (121 MHz, CD13) : 27.7.
73%
at 90 - 100℃; for 9h;
Preparation 5. [190] Diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide [191] N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (10.0 g), toluene (100.0 mL), and diphenyl(ethoxy)phosphorane (6.2 g) were added to a reactor. The reaction mixture was stirred at 90?100C for 9 hours and then water (80.0 mL) was added thereto. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane =1:1) to obtain diphenyl[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-ylmethyl]phosphine oxide as a white solid (9.4 g, yield 73%).[192] 1H-NMR, 400 MHz, CDCl3, ppm : 1.26(d, 6H), 3.41(m, 1H), 3.46(s, 3H), 3.51(s, 3H), 3.92(d, 2H), 6.95(m, 2H), 7.12(t, 2H), 7.57(m, 12H)
The reaction flask was evacuated to -0.098 MPa using a vacuum pump.Under this condition will be 23.02gDiphenylethoxyphosphine and 18.26g2,4,6-trimethylbenzoyl chloride was added to the reaction flask, and the reaction was started at a temperature of 40 C.During the reaction, the temperature was raised by 10 C every 20 minutes until the temperature was raised to 90 C.Then react at a constant temperature of 90 C for 8 h.The exhaust gas generated during the reaction is removed by vacuum to the ethyl chloride recovery system and used.After the reaction, 50% ethanol was added to crystallize.33.13 g of the target product TPO were obtained. The purity of the product was 99.2% and the yield was 95.1%.
R.1 Synthesis of o-(diphenylphosphinylmethyl)phenol
REFERENCE EXAMPLE 1 Synthesis of o-(diphenylphosphinylmethyl)phenol In a reactor equipped with a thermometer, a stirrer and a condenser were placed 99.2 g of o-(hydroxymethyl)phenol and 400 ml of tetrahydrofuran. They were made into a uniform solution. Thereto was added 184 g of ethyldiphenylphosphinite. The resulting mixture was subjected to reaction for 3 hr with heating and stirring. The reaction mixture was cooled and the resulting white crystal precipitate was separated by filtration and then dried to obtain 180 g of o-(diphenylphosphinylmethyl)phenol. Yield: 73% Melting point: 179° C.
A stirred mixture of methyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylate (12.0 g) in toluene (55 ml) was cooled to 10 C. and diisobutyl aluminium hydride (50 ml of a 1.5M solution in toluene) was added over two hours maintaining the temperature below 0 C. After addition, the mixture was stirred for 30 minutes at 0 C. Methanol (0.64 ml) was added to the mixture maintaining the temperature at 0 C. The mixture was then added over two hours to a stirred mixture of concentrated hydrochloric acid (23.3 ml), water (40.5 ml) and acetonitrile (24 ml) at 40 C., maintaining the temperature of the mixture at 40 C. After addition, the mixture was stirred at 40 C for a further 30 minutes and then purged with nitrogen (to remove any isobutane). The mixture was cooled to 20 C and allowed to stand for 20 minutes. The organic phase was separated and washed with a mixture of concentrated hydrochloric acid (0.7 ml) and water (30 ml). Acetonitrile (24 ml) was added to the organic phase and the mixture washed with a solution of sodium bicarbonate (0.038 g) in water (120 ml). The organic phase was heated to 40 C, and then from 40 C to 80 C using a nitrogen purge. The mixture was concentrated by distillation at atmospheric pressure, collecting 54 ml of distillate. Acetonitrile (24 ml) was added to the concentrated solution and phosphorus tribromide (1.2 ml) was added with stirring, maintaining the temperature of the mixture at 20 C. After addition, the mixture was stirred at 20 C for 30 minutes. The mixture was added to water (36 ml) over 30 minutes maintaining the temperature at 20 C. The mixture was stirred for 5 minutes and the organic phase separated. The organic phase was washed with a solution of sodium bicarbonate (0.027 g) in water (36 ml), followed by water (36 ml). The organic phase was distilled under reduced pressure until 29 ml of distillates was collected. The mixture was cooled to 60 C and ethyl diphenylphosphinite (7.47 ml) was added. The mixture was stirred at 60 C for 3 hours, then heated to reflux. Toluene (40 ml) was added and the mixture cooled to 0 C over 2 hours. The product was collected by filtration, washed with cold toluene (10 ml) and dried under vacuum at 50 C to give DPPO (14.66 g); 1H NMR (CDCl3, 270 MHz): 7.42 [m, 10H, P(C6H5)2], 7.12 [m, 2H, ArH], 6.92 [m, 2H, ArH], 3.92 [d, 2H, CH2P], 3.51, 3.46 (2 x s, 6H, NCH, SO2CH3], 3.43 [hept., 1H, CH(CH3)2], 1.25 [d, 6H, CH(CH3)2]
With cesium fluoride In acetonitrile at 20℃; for 16h; Inert atmosphere;
15 Triphenylphosphine Oxide (14)
General procedure: To a flame dried two-neck round-bottom flask containing CsF (5.50 equiv.) was added o-silyl aryl triflate (II) (1.00 equiv.) in acetonitrile, followed by addition of phosphorous compound of formula (III) (4.00 equiv.) in acetonitrile under argon atmosphere. The reaction mixture was stirred at room temperature and the progress was monitored by TLC. After completion of the reaction, acetonitrile was removed on rotary evaporator and the crude product was dried under high vacuum and purified by flash silica gel column using a gradient of ethyl acetate-petroleum ether to afford corresponding aryl-phosphorous compounds of formula (I) in good to excellent yields. 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Ethoxydiphenylphosphane (78 mg, 0.33 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf: 0.3 (1:3 EtOAc:Pet Ether); White Solid; 17.5 mg, 75%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.74-7.63 (m, 6H), 7.59-7.51 (m, 3H), 7.50-7.40 (m, 6H); 13C NMR (100 MHz, CDCl3, TMS) δ 132.5 (d, J=104.0 Hz), 132.1 (d, J=10.0 Hz), 131.9 (d, J=2.3 Hz); 128.5 (d, J=12.4 Hz); 31P NMR (162 MHz, CDCl3) δ 29.2; Mass (M+Na)+ 301; Known Compound, Lit. K. Prokop, D. Goldberg, J. Am. Chem. Soc. 2012, 134, 8014
Stage #1: 2,6-bis(aminomethyl)pyridine; chloroacetyl chloride With potassium carbonate In dichloromethane at 23℃; for 16h;
Stage #2: Ethyl diphenylphosphinite In o-xylene at 120℃; for 16h; Inert atmosphere;
Dissolve 46g of diphenylethoxyphosphine (0.20mol) in 200ml of toluene. Add 55.8g of 2,4,6-trimethyltrichloroacetophenone (0.21mol) to the organic phase dropwise. 50 , 1 hour; 50 to 60 , the reaction was incubated for 2-3.0 hours, and the reaction was completed when the GC detected diphenylethoxyphosphine content <1%, and the solution was desorbed under low pressure (by-product trichloropropane was stored by condensation ), Crystallized with ethyl acetate, suction filtered, and dried to obtain 55.6 g of a pale yellow solid with a yield of 81% and a purity of 99.2%.
With phosphotungstic acid In toluene at 100℃; for 1h; Inert atmosphere;
4-6; 2 Example 4
Under the protection of nitrogen, dissolve 0.5mol diphenylphosphonic acid and 0.8mol bromoethane in toluene, stir until uniform, then add 50g H3PW12O40, continue to stir and slowly raise the temperature to 100, keep the temperature and react for 1h, the reaction is complete After cooling the system to room temperature, distillation under reduced pressure gave the product ethyl diphenylphosphonate. The calculated yield was 95.4% and the measured purity was 99.0%.
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