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CAS No. : | 5324-30-1 | MDL No. : | MFCD00000239 |
Formula : | C6H14BrO3P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PINITSMLVXAASM-UHFFFAOYSA-N |
M.W : | 245.05 | Pubchem ID : | 79218 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | 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 |
---|---|---|
71% | With potassium carbonate In N,N-dimethyl-formamide at 153℃; for 15 h; | Potassium carbonate, 5.1 g (37 mmol), was added to a mixture of 1.8 g (7.41 mmol) of diethyl 2-bromoethylphosphonate and 1 g (7.41 mmol) of adenine in 20 mL of DMF. The mixture was refluxed for 15 h, the precipitate of potassium carbonate was filtered off, and the solvent was removed under reduced pressure. The residue was washed with acetone, and the white precipitate was filtered off and dried under reduced pressure (oil pump) until constant weight. Yield 1.6 g (71percent), mp >250°C. IR spectrum, ν,cm–1: 3143 (NH2), 1699 (C=C), 1029 (P=O). 1H NMRspectrum (DMSO-d6), δ, ppm: 1.24 t (6H, CH3, J =7.1 Hz), 2.55 d.t (2H, CH2, J = 18.2, 7.1 Hz), 4.004.09 m (4H, OCH2), 4.53 d.t (2H, CH2, J = 15.8,7.1 Hz), 8.15 s (1H, Harom), 8.24 s (1H, Harom). 31P NMR spectrum (DMSO-d6): δP 27.75 ppm. Mass spectrum: m/z 300.1 [M + H]+. Found, percent: C 44.33; H 5.81; N 23.18; P 10.54. C11H18N5O3P. Calculated, percent:C 44.15; H 6.06; N 23.40; P 10.35. M 299.3. 9-Ethyl-9H-purin-6-amine (2). The filtrate obtained after separation of compound 1 was left to stand for 12 h. The crystalline solid precipitated therefrom was filtered off and dried under reduced pressure (oil pump) until constant weight. Yield 0.1 g (9percent), mp 94-96°C. IR spectrum, ν, cm–1: 3270, 3105 (NH2), 1673 (C=C). 1H NMR spectrum (CDCl3), δ, ppm: 1.10 t(3H, CH3, J = 7.4 Hz), 3.67 q (2H, CH2, J = 7.3 Hz),7.48 s (1H, Harom), 7.53 s (1H, Harom). Mass spectrum: m/z 202 [M + K]+. Found, percent: C 51.68; H 5.70;N 43.17. C7H9N5. Calculated, percent: C 51.52; H 5.56;N 42.92. M 163. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In benzene for 1h; Reflux; | |
90% | With potassium hydroxide In ethanol Reflux; | 3.ii A 150 ml two-necked round bottom flask was filled with EtOH (85 ml). KOH pellets (2.52 g, 0.045 mol) were added. The mixture was stirred in an ice bath until complete KOH dissolution. Diethyl (2-bromoethyl)phosphonate (1) (8.1 ml, 0.045 mol) was added dropwise (30 minutes) by means of an equalizing pressure funnel. Meanwhile a white solid formed. The mixture was refluxed for 15 minutes, and, after cooling, was filtered using a frit. The white solid was washed with absolute EtOH and the filtrate was roto-evaporated, and finally dried under a vacuum pump for 15 minutes. The residue was distilled with a micro-distillator. The first fraction (43° C., 0.5 mmHg) corresponded to pure diethyl vinylphosphonate (3) (yield 90%).1H NMR (CDCl3): δ(ppm)=5.99-6.36 (3H), 4.09 (m, 4H), 1.33 (t, 6H).31P{1H} (CDCl3): δ(ppm)=18.1. |
90% | With potassium hydroxide In ethanol for 0.25h; Heating / reflux; | 3.ii (ii) Synthesis of diethyl vinylphosphonate (3); A 150 ml two-necked round bottom flask was filled with EtOH (85 ml). KOH pellets (2.52 g, 0.045 mol) were added. The mixture was stirred in an ice bath until complete KOH dissolution. Diethyl (2- bromoethyl) phosphonate (1) (8.1 ml, 0.045 mol) was added dropwise (30 minutes) by means of an equalizing pressure funnel. Meanwhile a white solid formed. The mixture was refluxed for 15 minutes, and, after cooling, was filtered using a frit. The white solid was washed with absolute EtOH and the filtrate was roto-evaporated, and finally dried under a vacuum pump for 15 minutes. The residue was distilled with a micro-distillator. The first fraction (43°C, 0.5 mmHg) corresponded to pure diethyl vinylphosphonate (3) (yield 90%) .IH NMR (CDC13) : δ(ppm) .= 5.99-6.36 (3H), 4.09 (m, 4H), 1.33 (t, 6H) . 31P{1H} (CDC13) : δ(ppm) = 18.1. |
86% | With orthoformic acid triethyl ester for 2h; Heating; | |
86% | With potassium hydroxide In ethanol at 20℃; for 1.25h; Reflux; | 4.1.3. Preparation of diethyl vinylphosphonate Diethyl 2-bromoethylphosphonate (24.5 g, 0.1 mol) was slowly added to a cold solution of KOH (5.6 g, 0.1 mol) in 150 ml of ethanol. The reaction mixture was stirred at room temperature for 1 h then heated to reflux for 15 min. The formed solid was filtered off and washed with ethanol. Ethanol was removed under vacuum and the remaining oil was distilled under reduced pressure. |
83% | With triethylamine In water; acetone for 4h; | |
With potassium hydroxide | ||
With triethylamine; benzene | ||
With diethylamine; toluene | ||
10 g | With triethylamine In benzene for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | In lithium hydroxide monohydrate at 20℃; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | for 2h; Reflux; | 1.i 1,2-dibromoethane (69 ml, 0.8 mol) was poured into a two-necked 150 mL round-bottom flask. Triethylphosphite (34.3 ml, 0.2 mol) was added under stirring and the mixture was then refluxed for 2 hours. The excess of 1,2-dibromoethane was removed by rotary evaporation under gentle warming at 60-70° C. The residue was distilled under reduced pressure (2 mmHg, 95-105° C. or 1 mmHg, 75° C.). Yield 95%.1H NMR (CDCl3), δ(ppm)=4.01 (m, 4H); 3.42 (q, 2H); 2.27 (m, 2H); 1.22 (t, 6H).31P{1H} (CDCl3): δ(ppm)=26.4. |
95% | for 2h; Heating / reflux; | 1.i Example 1; Synthesis of bis [ (dimethoxypropylphosphino) ethyl] ethoxyethylamine (PNP5) by the method of the present invention(i) Synthesis of diethyl (2-bromoethyl) phosphonate (1) 1, 2-dibromoethane (69 ml, 0.8 mol) was poured into a two-necked 150 mL round-bottom flask. Triethylphosphite (34.3 ml, 0.2 mol) was added under stirring and the mixture was then refluxed for 2 hours. The excess of 1 , 2-dibromoethane was removed by rotary evaporation under gentle warming at 60-70 °C. The residue was distilled under reduced pressure (2mmHg, 95-1050C or lmmHg, 75°C). Yield 95%.IH NMR (CDC13) , δ(ppm) = 4.01 (m, 4H); 3.42 (q, 2H); 2.27 (m, 2H) ; 1.22 (t, 6H) .31P{1H} (CDC13) : δ(ppm) = 26.4. |
83% | at 160℃; for 3h; | Diethyl (2-bromoethyl)phosphonate. The mixture of1,2-dibromoethane (75.2 g, 0.4 mol) and triethylphosphite (16.6 g, 0.1 mol) wasplaced in a 100-ml three-necked flask, then heated at 160 oC for 3h. The resulted solution was distilled under reduced pressure to give diethyl(2-bromoethyl)phosphonate as a colorless liquid (18.6 g, 83%). |
80% | at 160℃; for 4h; Inert atmosphere; | |
79% | at 160℃; for 4h; | |
74% | at 206℃; | |
70% | at 160℃; for 3.5h; | |
70% | at 160℃; for 1h; | Preparation of diethyl 2-bromoethylphosphonate (1) 1,2-dibromoethane(150 mL, 1.75 mol) was placed into a 250 mL three-neckedask, andthe solution was slowly heated to 160 °C withvigorous stirring. Triethylphosphite (60 mL, 0.35 mol) was added dropwise over the course of 1h, andthe reaction was monitored by 31P NMR spectrum.Whenthe peak at δ 137ppmdisappeared, the reaction wasfinished. The solution wascooled to roomtemperature and distilledat reducedpressure(1-5 mbar at 110-128 °C, ref.1 105-130°C) togivecolourlessoil1 (59.8 g, 70.0%). 1H NMR (CDCl3)d = 4.12 (m,4H), 3.54 (m, 2H), 2.39 (m, 2H), 1.34 (t, J = 14.4 Hz, 1H).13C NMR (CDCl3)d = 65.6, 48.2 (d, J =10.0 Hz), 29.3 (d, J =140.0 Hz), 19.2.31P NMR (CDCl3) d = 25.1. |
68% | at 150 - 160℃; for 13h; | |
66.7% | at 160℃; for 3h; | |
65% | 1.) 120 deg C; 2.) 160 deg C, 2 h; | |
64% | at 160℃; for 4h; | |
64% | at 140℃; for 0.5h; | 1 Preparation Example 1: Preparation of DL-2-amino-4-phosphonobutanoic acid hydrate Triethyl phosphite (40.0 ml, 233 mmol) was added to 1,2-dibromoethane (80 ml, 928 mmol), the mixture was raised in temperature up to 140° C. with stirring on an oil bath, heated at the same temperature for 30 minutes, and naturally cooled. After cooling down to around 40° C., pressure reduction was started. The pressure reduction and heating were gradually intensified, to distill off excess dibromoethane and by-products such as ethyl bromide. The pressure reduction was then further intensified to a degree of vacuum of about 1 mmHg, and distillation was performed with heating at about 130° C. This gave colorless, odorless, oily diethyl 2-bromoethylphosphonate (36.3 g, yield: 64%). |
62% | at 160℃; for 4h; | 4.1.2. Preparation of diethyl 2-bromoethylphosphonate Triethylphosphite (35 ml, 0.2 mol) was mixed with 1,2-dibromoethane (69 ml, 0.8 mol) in a round-bottom flask equipped with a reflux condenser, heated at 160 °C and stirred for 4 h. The reaction mixture was cooled and purified by distillation at reduced pressure. |
61% | at 160℃; for 4h; | |
58.5% | at 150℃; | |
at 160℃; | ||
at 160℃; for 0.333333h; Microwave irradiation; | 22.1 Example 22Table 1Compound 22Synthesis of 2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethylphosphonic acid (22)Step 1: diethyl 2-bromoethylphosphonateCommercially available 1,2-dibromoethane (1.0 equiv.) and triethyl phosphite (1.0 equiv.) were heated with microwave irradiation at 160° C. for 20 minutes. The resulting residue was purified by reverse phase high performance liquid chromatography (HPLC) (0.035% TFA in ACN: 0.05% TFA in H2O, C18 column) to give diethyl 2-bromoethylphosphonate as a colorless liquid. | |
for 5h; Reflux; | ||
at 140℃; for 5h; | ||
In neat (no solvent) for 0.5h; Reflux; | ||
at 160℃; for 4h; | ||
at 110℃; | ||
With trifluoroacetic acid at 160℃; for 0.333333h; Microwave irradiation; | 22.1 Step 1: diethyl 2-bromoethylphosphonate Commercially available 1,2-dibromoethane (1.0 equiv.) and triethyl phosphite (1.0 equiv.) were heated with microwave irradiation at 160° C. for 20 minutes. The resulting residue was purified by reverse phase high performance liquid chromatography (HPLC) (0.035% TFA in ACN: 0.05% TFA in H2O, C18 column) to give diethyl 2-bromoethylphosphonate as a colorless liquid. | |
at 140℃; | General procedure for synthesis of bromo-alkyl phosphonate (7c-7f) General procedure: Compounds 7c-7d were synthesized from corresponding dibromoalkane and triethylphosphite. 1 equivalent (20 mmol) of corresponding dibromoalkane and 1 equivalent (20 mmol) of triethyl phosphite was refluxed at 140°C overnight. The reaction mixture was cooled to room temperature and the compounds 7c-7f were purified by passing through a short column packed with silica gel and used immediately after removal of solvents. Compounds 7a, and 7b are commercially available compounds and 7c-7f are previously reported compounds 4-6. | |
36.3 g | at 140℃; for 0.5h; | 3 Example 3 Triethyl phosphite (40.0 ml, 233 mmol) was added to 1,2-dibromoethane (80 ml, 928 mmol), heated to 140 ° C. in an oil bath under stirring, heated at the same temperature for 30 minutes, did. After cooling to around 40 ° C., pressure reduction was started. Gradual depressurization and heating were intensified, by-products such as ethyl bromide and excess dibromoethane were distilled off. Thereafter, the degree of vacuum was further raised (about 1 mmHg) and heated and distilled at about 130 ° C. to obtain diethyl 2-bromoethylphosphonate (36.3 g) in the form of colorless odorless oil. |
at 150 - 160℃; | Compounds 4a-4d (general procedure). General procedure: A mixtureof triethyl phosphite (0.41 mL, 2.5 mmol) and 1,2-dibromoethane(3a), oxalyl chloride (3b), chloroacetylchloride (3c), or ethyl chloroacetate (3d) (3.5 mmol)was heated under reflux at 150-160°C for 3-5 h.Excess reactants were removed under reduced pressure,a solution of pyranopyrimidine 2 (0.74 g, 2.5 mmol)in THF (25 mL) containing sodium hydride (0.07 g,3 mmol) was added to the residue, and the mixture wasfurther heated at 55-60°C for 10-15 h. After completionof the reaction, the solvent was removed underreduced pressure, and the residue was recrystallizedfrom an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium carbonate In N,N-dimethyl-formamide at 40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; for 24h; | ||
In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride; In toluene; at 110℃; for 24h; | Diethyl 2-bromoethylphosphonate (25.0 g, 102 mmol) was combined with toluene (70 mL), diethyl carbonate (40 mL), diethyl acetamidomalonate (16.9 g, 77.6 mmol), and 60% sodium hydride (4.40 g, 110 mmol) washed with hexane, followed by refluxing at 110 C. After being refluxed for 24 hours, the mixture was cooled down to room temperature, filtered through Celite to remove solids, and the filtrate was concentrated under vacuum. This gave brown, oily diethyl 2-acetamido-2-[2-(diethoxyphosphoryl)ethyl]malonate (33.3 g, in quantitative yield). |
33.3 g | With sodium hydride; Diethyl carbonate; In hexane; toluene; mineral oil; at 110℃; for 24h; | To toluene (70 mL), diethyl carbonate (40 mL), diethyl acetamidomalonate (16.9 g, 77.6 mmol), and 60% sodium hydride (4.2 mL) were added to diethyl 2-bromoethylphosphonate (25.0 g, 40 g, 110 mmol) was washed with hexane was charged,And refluxed at 110 C.After refluxing for 24 hours,After cooling to room temperature,Filtration was carried out using celite,By concentrating the resulting filtrate under reduced pressure,Brown oilyTo obtain diethyl 2-acetamido-2- [2- (diethoxyphosphoryl) ethyl] malonate (33.3 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium azide In N,N-dimethyl-formamide; acetonitrile for 7h; Heating; | |
92% | With sodium azide In water; N,N-dimethyl-formamide for 48h; Reflux; | Preparationof diethyl 2-azidoethylphosphonate Asolution of sodium azide (1.3 g, 20.0 mmol) in water (5.0 mL) was added to avigorously stirred solution of diethyl 2-bromoethylphosphonate(2.4 g, 10.0 mmol) in DMF (20 mL) at roomtemperature.The mixture solution was stirred over 48 h at room temperature.The reaction course was monitored by 31PNMR. Thereaction was finished, and thesolution was extracted with dichloromethane (30 mL × 3), and the combined organic phase was dried over Na2SO4. Thesolvent was removed in vacuoand thecrude product was purified by flash column chromatography on silica gel usingEtOAc:hexane (1:1) as the eluent to afford the colorless oil2 (1.9 g, 92%).IR (KBr) ν (cm-1) =2103, 1248, 1028, 965. 1H NMR(CDCl3)d = 1.32 (t, J= 7.1 Hz, 6H, CH3), 2.04 (dt, J= 18.6 Hz, J = 7.7 Hz, 2H, PCH2), 3.52 (dt, J= 7.8 Hz, J = 7.7 Hz, 2H, NCH2), 4.07-4.11 (m, 4H, OCH2). 13C NMR(CDCl3) d = 61.7, 45.1 (d, J =10.0 Hz), 26.4 (d, J =140.0 Hz), 16.2. ESI MS: m/z = 208.0 [M+H]+.Spectroscopic data was in accordance with that reported literature.2 |
89% | With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water for 144h; Sealed tube; | i (i) Diethyl 2-azidoethylphosphonate 115 Diethyl 2-bromoethylphosphonate (500 mg, 2 mmol) was dissolved in DCM (10 mL) with tetrabutylammonium bisulfate (2.04 g, 6 mmol). A solution of sodium azide (1.30 g, 20 mmol) in distilled water was added (10 mL) and the resulting mixture was stirred vigorously in a sealed flask. The reaction progress was monitored by TLC. After 6 days, the product was extracted with diethyl ether (2×10 mL), dried over Na2SO4, filtered, and the solvent evaporated. The crude residue was purified via flash chromatography (1:1→3:1 EtOAc-hexanes) to afford the title compound (370 mg, 89%) as a white solid. Rf=0.225 (2:1 EtOAc-hexanes); IR vmax (neat) 2099, 1240, 1019, 957; 111 NMR (400 MHz, CDCl3) δ 1.34 (6H, t, J=6.9 Hz, CH3), 2.07 (2H, dt, J=18.6 Hz, J=7.8 Hz, CH2), 3.55 (2H, dt, J=12.6 Hz, J=7.5 Hz, CH2), 4.13 (4H, m, CH2); 13C NMR (400 MHz, D2O) δ 16.1, 24.72, 26.58, 45.13, 61.60; m/z (ESI) 208.08 [M+H]+, 230.07 [M+Na]+. The 1H and 13C NMR and MS data obtained were in agreement with that reported in the literature (Brunet, E. et al. Tetrahedron Lett. 2009, 50, 5361-5363). |
87% | With sodium azide; tert-butylammonium hexafluorophosphate(V) In tetrahydrofuran at 60℃; for 48h; | |
85% | With sodium azide; tetrabutylammomium bromide In tetrahydrofuran for 48h; Reflux; | |
74% | With azide exchange resin on amberlite at 20℃; for 20h; | |
60% | With sodium azide In water at 100℃; for 0.5h; Microwave irradiation; | General procedure for the preparation of products 5a-e to 7a-e General procedure: Dialkyl ω-bromoalkylphosphonate (2.0 mmol) was added to the solution of NaN3 (3.0 mmol, 1.5 eq) in H2O (3 mL) placed in 10-mL pressure vial, equipped with magnetic stirrer. The reaction was carried under MW conditions. After that, reaction mixture was extracted with Et2O (4 10 mL). The combined organic layers were washed successively with water (5 mL) and brine (5 mL), dried over anhydrous MgSO4, and evaporated under reduced pressure. The rest of the volatile material was removed at 35 °C / 27 Pa to give pure products 5-7. If necessary, products 5-7 were subjected to flash chromatography on silica gel. |
46% | With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In toluene | |
With sodium azide | ||
With Merrifield resin supported tetra-alkyl ammonium azide In dimethyl amine at 25℃; for 72h; | ||
With sodium azide; 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate at 80℃; for 2h; | ||
With sodium azide; tetrabutylammomium bromide In tetrahydrofuran for 48h; Reflux; | Diethyl (2-bromoethyl)phosphonate (2.5 g, 10 mmol) was dissolved in THF (50 mL).Tetrabutylammonium bromide (10 g, 30 mmol; TBAB) was added followed by sodium azide (6.5 g).The reaction mixture was refluxed for 2 days. The reaction mixture was poured in EtOAc (250 mL).Water (125 mL) was added. The slightly orange organic layer was separated and dried with Na2SO4.Evaporation under reduced pressure afforded the crude product as an oil (3.6 g). According to NMRanalysis ca. 25% product was present together with 75% TBAB. Mass only: M+1 208 found and 242(M+ Bu4N+). Diisopropyl ether (100 mL) was added to the crude oil. After mixing for 2 minutes the upper solution was decanted from the oily precipitate. Evaporation of the diisopropyl ether solventafforded diethyl (2-azidoethyl)phosphonate as a clear colorless oil, pure according to NMR analysis. | |
With sodium azide; tetra(n-butyl)ammonium hydrogensulfate In methanol at 65℃; | Synthesis of Diethyl (2-Azidoethyl)phosphonate (3) Diethyl (2-bromoethyl)phosphonate (2.00 mL, 11 mmol) and TBAHS (5.6 g, 16.5 mmol) were dissolved in methanol (MeOH; 50 mL). NaN3 (2.9 g, 44 mmol) was added and the reaction mixture was stirred at 65°C under a reflux condenser for 17 h. The solvent was evaporated to dryness and the residue diluted with Et2O (30 mL) and filtered through Celite. The filtrate was then washed with H2O (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.44 g, 63 %) as a yellow oil that was not purified further. Caution: azides are potentially explosive. δH (CDCl3, 400 MHz) 4.11 (4H, m), 3.53 (2H, dt, J 10.0, 6.4), 2.08 (2H, dt, J 10.4, 4.4), 1.33 (6H, t, J 7.9). δC (CDCl3, 75 MHz) 61.9, 45.2, 24.4, 16.2. The NMR data closely matched that previously reported.[26] | |
With sodium azide In ethanol Inert atmosphere; Reflux; | ||
With sodium azide In N,N-dimethyl-formamide at 80℃; for 12h; | ||
With sodium azide In acetone at 60℃; Inert atmosphere; | General procedure for synthesis of azido-alkyl phosphonate (8a-8f) General procedure: 1-Bromoalkylphosphonate (3 mmol, 1 equiv.) was heated with sodium azide (9 mmol, 3 equiv.) in acetone and at 60°C overnight under nitrogen atmosphere for overnight. The reaction mixture was cool to room temperature and filtered through filter paper. The filtrate was concentrated, and the residue was re-dissolved in 30 mL dichloromethane and washed with 2x40 mL water. After evaporation of solvents, the azidoalkylphosphonate was obtained as an oil. Compound 8a-8c, and 8f are previously reported compounds 4, 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h; | |
26% | Stage #1: (2R)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate; Diethyl vinylphosphonate In tetrahydrofuran; hexane at -78 - 20℃; | 1a 1a) Diethyl {2-[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]ethyl}phosphonate [Show Image] nBuLi (6.51 mL, 2.5 mol/L in hexanes, 16.3 mmol) was added at -78°C to a solution of (2R)-(-)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazin (2.91 mL, 16.3 mmol) in dry THF (30 mL). After 30 min a solution of diethyl (2-bromoethyl)phosphonate (2.84 mL, 15.5 mmol) and diethyl vinylphosphonate (0.13 mL, 0.81 mmol) in dry THF (20 mL) was added drop wise to the mixture. After further 10 min the mixture was warmed to r.t. and concentrated under reduced pressure. The residue was taken up in water (50 mL) and the solution was extracted with ethyl acetate (3 x 50 mL). The combines organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Hex/EE). Yield: m = 1.50 g, 4.31 mmol, 26%. MS (ESipos): m/z = 349 [M+H]+ 1H-NMR (300MHz, CHLOROFORM-d): δ [ppm]= 0.68 (d, 3H), 1.02 (d, 3H), 1.31 (td, 6H), 1.65 - 1.82 (m, 2H), 1.82 - 2.00 (m, 1H), 2.03 - 2.36 (m, 2H), 3.66 (s, 3H), 3.69 (s, 3H), 3.94 (t, 1H), 3.98 - 4.17 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium iodide In acetone at 75℃; for 24h; Inert atmosphere; | |
93% | With sodium iodide In acetone Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium carbonate In ethanol Heating; | |
With sodium carbonate In dichloromethane; chloroform | 12 [2-(9,10-Dioxo-2,7-diazabicyclo[6.2.0]dec-1(8)-en-2-yl)ethyl]phosphonic acid A solution of (4-aminobutyl)carbamic acid 1,1-dimethylethyl ester (13.3 g, 71 mmol), sodium carbonate (11.25 g, 106 mmol) and diethyl 2-bromo-ethylphosphonate (20 mL, 104 mmol) in absolute ethanol (150 mL) was prepared under nitrogen. This mixture was refluxed overnight and was then concentrated in vacuo. The residue was dissolved in chloroform (150 mL) and then preadsorbed onto silica gel and purified by flash chromatography (7 cm diameter, gradient elution with 5-30% methanol in dichloromethane) to yield [4-[[2-(diethoxyphosphinyl)ethyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester as a colorless oil (13.7 g, 55%); MS (+FAB): 353 MH+, 100), 150 (68), 56 (83); 1 H NMR (CDCl3, 400 MHz): δ 5.01 (br s, NH), 4.17-4.03 (m, 4H),3.15-3.08 (m, 2H), 2.92 (d of t, J=15 and 7.5 Hz, 2H), 2.84 (br s, NH), 2.66 (br t, J=7 Hz, 2H), 2.02 (d of t, J=18 and 7.5 Hz, 2H), 1.56-1.52 (m, 4H), 1.43 (s, 9H), 1.33 (t, J=7 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In dichloromethane; chloroform; | A solution of <strong>[144912-84-5](3-amino-2-hydroxypropyl)carbamic acid 1,1-dimethylethyl ester</strong> (7.73 g, 41 mmol), sodium carbonate (6.52 g, 62 mmol) and diethyl 2-bromoethylphosphonate (11.8 mL, 65 mmol) in absolute ethanol (150 mL) was prepared under nitrogen. This mixture was refluxed overnight and was then concentrated in vacuo. The residue was dissolved in chloroform (150 mL) and then preadsorbed onto silica gel and purified by flash chromatography (7 cm diameter, gradient elution with 2.5-20% methanol in dichloromethane) to yield [3-[[2-(diethoxyphosphinyl)ethyl]amino]-2-hydroxypropyl]carbamic acid 1,1-dimethylethyl ester as a colorless oil (11.16 g, 77%); IR (neat, cm-1): 3320, 1710, 1250, 1170, 1040; MS (+FAB): 355 (MH+, 68), 255 (90), 58 (100); 1 H NMR (CDCl3, 400 MHz): delta 5.23 (br s, NH), 4.16-4.05 (m, 4H), 3.77 (m, 1H), 3.32-2.90 (m, 4H), 2.73 (d of d, J=12 and 3.5 Hz, 1H), 2.58 (d of d, J=12 and 8.5 Hz, 1H), 2.00 (d of t, J=18 and 7 Hz, 2H), 1.43 (s, 9H), 1.32 (t, J=7 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In acetonitrile at 65℃; for 120h; | |
In water for 72h; Heating; | ||
at 20℃; for 12h; | 2 Comparative Example 2 4,4'-bipyridinium-bis(diethyl phosphonic acid) Dichloride Salt (VIII) (PVP) 3.12 g of 4,4'-Dipyridyl was mixed with 10.1 g of diethyl-(2-bromoethyl) phosphonate and the mixture was reacted for 12 hours at room temperature. 500 ml of cold diethylether was added thereto, followed by stirring for additional 1 hour and filtration of precipitate. The precipitate was washed with 50 ml of diethylether three times and dried under vacuum to obtain 11.6 g of compound (VII). 11.6 g of compound (VII) obtained as described above was dissolved in 100 ml of 6N HCl and reacted under reflux for 24 hours. After evaporation of the solvent, recrystallization was performed by using H2O, MeOH and THF to obtain 6.85 g of compound (VIII). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In water at 80℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: [(Z)-2-(Diphenyl-phosphinoyl)-1-methyl-vinyl]-p-tolyl-amine With methyllithium In tetrahydrofuran; diethyl ether at -78℃; for 1h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran; diethyl ether at 20℃; for 12h; Stage #3: With sodium cyanoborohydride; zinc(II) chloride In ethanol for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: [(Z)-2-(Diphenyl-phosphinoyl)-1-methyl-vinyl]-p-tolyl-amine With methyllithium In tetrahydrofuran; diethyl ether at 0℃; for 1h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: [(E)-2-(Diphenyl-phosphinoyl)-1-methyl-vinyl]-((S)-1-phenyl-ethyl)-amine With methyllithium In tetrahydrofuran; diethyl ether at 0℃; for 1h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 2-N-(diphenylmethyl)aminopropyldiphenylphosphine oxide With methyllithium In tetrahydrofuran; diethyl ether at -78℃; for 1h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran; diethyl ether at 20℃; for 12h; Stage #3: With sodium cyanoborohydride; zinc(II) chloride In ethanol for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: 2-N-(diphenylmethyl)aminopropyldiphenylphosphine oxide With methyllithium In tetrahydrofuran; diethyl ether at 0℃; for 1h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hypophosphite; air; triethyl borane In methanol; hexane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With selenium; sodium tetrahydroborate In ethanol at 40℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: m-trimethylsilylbenzyl phenyl sulfone With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | Stage #1: 1-Butylimidazole; diethyl 2-bromoethylphosphonate at 80℃; for 24h; Stage #2: With sodium tetrafluoroborate In acetone at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.3% | Stage #1: 1-Butylimidazole; diethyl 2-bromoethylphosphonate at 80℃; for 24h; Stage #2: With ammonium hexafluorophosphate In acetone at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: diphenylphosphane With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 30h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran; hexane at -78 - 20℃; for 2.33333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.24% | Stage #1: 4,4'-bipyridine; diethyl 2-bromoethylphosphonate In water for 72h; Heating / reflux; Stage #2: With hydrogenchloride; water for 24h; Heating / reflux; | 1.b (b) An n-type redox chromophore, bis-(2-phosphonoethyl)-4,4'-bipyridinium dichloride was prepared by adding 4,4'-bipyridine (4.4 g) and diethyl-2-ethylbromo-phosphonate (15.0 g) to water (75 ml). The reaction mixture was refluxed for 72 h and allowed to cool. Following addition of conc. hydrochloric acid (75 ml) the reaction mixture was refluxed for a further 24 h. To recover the product, the reaction mixture was concentrated to 50 ml, isopropyl alcohol (200 ml) added drop-wise, stirred on ice for one hour and filtered. The white crystalline product was washed with cold isopropyl alcohol and air dried to give pure bis-(2-phosphonoethyl)-4,4'-bipyridinium dichloride (12.72 g, 84.24% yield). Calculated for bis-(2-phosphonoethyl)-4,4'-bipyridinium dichloride (C14H20N2Cl2O6P2): C, 37.77; H, 4.53; N, 6.29. Found: C, 35.09; H, 4.49; N, 6.09. 1H NMR (water-d2): δ 2.31-2.43 (m, 4H); δ 4.68-4.80 (m, 4H); δ 8.33 (d, unresolved metacoupling, 4H); δ 8.94 (d, unresolved metacoupling, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | In N,N-dimethyl-formamide; at 20℃; for 12.0h; | To a stirred solution of <strong>[737-31-5]sodium diatrizoate</strong> (7.1g, 11.2 mmol) in dry dimethylformamide (50 ml) at room temperature under a blanket of argon was added a solution of diethyl 2-bromoethylphosphonate (3.02g, 12.3 mmol, 1.1 eq.) in dimethylformamide (10 ml). After stirring for 12 hours, the solvent was evaporated under vacuum to give a white solid that was washed with 300 ml of saturated aqueous NaHCO3, and then extracted with a 2:1 mixture of chloroform-ethanol (3 x 200 ml). The organic extract was dried (MgSO4), filtered, and evaporated under vacuum to give 3.61g (41%) of product as a white solid. Recrystallization from acetonitrile gave analytically pure material; mp 249-251C; MH+ (779). The 1H-NMR (300 MHz) spectrum was consistent with the desired material. Calculated for C17H22I3PN2O7: C 26.24; H 2.85; I 48.93; N 3.60; Found: C 26.26; H 2.70; I 49.05; N 3.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS); | EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 100 - 110℃; for 26.5h; | 1.1 equivalents of diethyl 2-bromoethyl phosphonate in N, N-dimethyformamide (DMF) was added to a solution of 1 and 3 equivalents of powdered anhydrous K2CO3 in DMF and the reaction mixture was heated to 100-110C within 30 minutes. The reaction mixture was allowed to stir at 100-110C for 26 h under a N2 atmosphere and the reaction was monitored by ESI-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, and evaporated under reduced pressure. The product was dissolved in ethylacetate and washed several times with 100mL of water and the organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness, yielding 93% of 2. ESI-MS(+): found: 701 [M+Na]+; calculated for C32H63N4O9P: m/z 678. 1H NMR (250 MHz CDCl3): 1.35 (t, 3H), 1.45(s, 27H), 1.87 (mixed d and t, 2H), 2.41 (t, 2H), 2.51 to 3.29 (m, 22H), 4.07 (q, 2H); 13C NMR (CDCl3): 14.79 (C-20); 23.01 (C-18); 28.81 (C-16); 48.08 (C-17); 50.10 (C9, C-11); 52.4 to 52.7 (C-2 to C-6); 56.62 (C-8, C-12); 57.21 (C-13); 62.3 (C-19); 81.79 (C-15); 169.59 (C-14); 31P NMR (CDCl3): 18.52. Elemental analysis: calculated (found) for C32H63N4O9P: C, 56.62 (56.67); H, 9.35 (9.39); N, 8.25 (8.30); O, 21.21 (21.26); P, 4.56 (4.12). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium hydrogencarbonate In water at 95℃; | 15 Example 15: Synthesis of di-t-butyl (α4.3-0-isopropylidene-3-hvdroxy-4- hvdroxymethyl-2-methyl-5-pyridylV3-azabutylphosρhonate(α4,3-OτIsopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5- pyridyl)methylbromide (Imperalli et al, J. Org. Chem., 60, 1891-1894 (1995)) ( 1.08 g. 4.0 mmol) in anhydrous DMF (20 ml) was treated with sodium azide (260 EPO A2005/001470mg, 4.0 mmol) at room temperature. After one hour stirring at room temperature, the solution was extracted with diethyl ether (5 x 20 mL). The combined extracts were washed with water (10 mL) , and brine (10 mL) and dried (MgSCU). The solvent was evaporated and the crude product was purified by chromatography on silica gel using ethyl ether: hexanes (2:1) as eluent to give the azide as a colorless liquid (552mg, 60%).1H NMR (CDC13, TMS) 1.57 (s, 6H)52.42 (s, 3H)5 4.23 (s, 2H)54.86 (s, 2H)57.96 (S5 IH).The purified azide (100 mg5 0.4 mmol) was dissolved in 95% ethanol and hydrogenated at 1 aim in presence of Lindlar catalyst (50 mg) for one hour. The catalyst was removed by filtration (Celite), and the solvent removed to give the crude amine. Purification by chromatography on silica gel using CH2Cl2:MeOH (5:1) as eluent gave the product (80 mg5 82% ) IHNMR (CD2Cl2) 1.53 (s, 6H)5 2.34 (s5 3H)5 3.72 (s, 2H)5 4.91 (s, 2H)5 5.31 (s, 2H)5 7.93 (s, IH).The (α453-O-Isopropylidene-3-hydroxy-4-hydroxymethyl-2-methyl-5- pyridyl)methylamine5 from above, (416 mg, 2 mmol) was heated in saturated, aqueous sodium bicarbonate solution (10 mL) to 950C, followed by slow addition of diethyl 2-bromoethylphosphonate (0.09 mL, 0.5mmol) and the reaction stirred at 95°C overnight. The solution is evaporated using toluene to codistill the water. The crude product is triturated with ethyl acetate to dissolve the crude organic product. Chromatography on silica gel using methylene chloride:methanol:hexanes (5:1:5) gave 76 mg (41%).1HnTnT (CDCl3, TMS) 1.27 (t, 6H)5 1.51 (s, 6H)5 1.91 (t, 2H), 2.35 (s, 3H)5 2.85 (t, 2H), 3.62 (S5 2H)5 4.03 (m5 4H)5 4.91 (s, 2H)5 7.88 (s, IH). 31P NMR (H-decoupled, CDCl3): 31.00 (s). This structure can be represented by formula: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 90℃; for 26h; | Synthesis of Diethyl 2-(3-Ethynylphenylamino)ethylphosphonate Synthesis of Diethyl 2-(3-Ethynylphenylamino)ethylphosphonate 3-Ethynyl aniline (2.36 g, 22.1 mmol), diethyl 2-bromoethylphosphonate (5.41 g, 22.1 mmol) and potassium carbonate (3.1 gm, 22.1 mmol) were heated at 90° C. in anhydrous acetonitrile (40 mL) for 26 h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluding with 1:1 ethyl acetate:hexanes followed by 97:3 methylene chloride:methanol to provide diethyl 2-(3-ethynylphenylamino)ethylphosphonate (450 mg) as a yellow oil. 1H NMR (CDCl3) δ 7.15 (t, 1H), 6.83 (d, 1H), 6.70 (br s, 1H), 6.60 (m, 1H), 4.10 (m, 4H), 3.41 (m, 2H), 3.00 (s, 1H), 2.10 (m, 2H), 1.35 ppm (m, 6H). MW=281 confirmed by LC-MS, tr=11.65 min (Method Y) MH+=282. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-Diazabicyclo<5.3.0>dec-7-en In N,N-dimethyl-formamide for 5h; Heating / reflux; | 17 Example 17; Preparation of N-r2-(diethoχyphosphoryl)ethvn-1.4,7, 10- tetraazacvclododecane-molvbdenum-tricarbonyl complex and f2-(1,4.7,10- tetraazacvclododec-1-yl)-ethvϖ-phosphonic acid via 1,4.7.10- tetraazacvclododecane-molvbdenum-tricarbonyl complex; 1,4,7,10-Tetraazacyclododecane 0,4 g (2,3 mmol) and molybdenum hexacarbonyl 0,6 g (2,3 mmol) in dry dibutyl ether (20 ml) were heated at reflux under argon for 2 h to give a bright yellow precipitate of the 1,4,7,10- EPO tetraazacyclododecane-molybdenuin-tricarbonyl complex which was filtered under argon and dried in vacuo.into a 25 ml four necked reaction bottle equipped with septum, a syringe, reflux condenser with argon overpressure inlet adapter and magnetic stirrer apparatus there were placed 70,4 mg (0,2 mmol) of 1 ,4,7,10- tetraazacyclododecane-molybdenum-tricarbonyl complex and 8 ml of well dried dimethylformamide. After the solution was complete, 2,5,6,7,8,9- hexahydro-3H-imidazo[1,2-a]azepine (28 mg) was added. To this solution was added very slowly 49 mg (0,2 mmol) (2-bromoethyl)phosphonic acid diethyl ester in 5 ml of dried acetonitrile at reflux temperature. After addition, the mixture was refluxed under argon next 5 hours. The solvent was removed in vacuo and the residue taken up in degassed 5ml 20% aqueous hydrochloride acid. The resulting acidic mixture was oxidized in air until no more carbon monoxide evolved, and then it was washed with chloroform (3x 10 ml). Aquoeous phase was evaporated at vacuo. The residual oil was dissolved in 35% hydrochloric acid and refluxed over night and evaporated to dryness and separated by chromatography on alumina. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 70℃; for 3h; | 1.ii In a 50 mL two-necked round bottom flask equipped with an automatic stirrer and heater, and with a condenser, diethyl (2-bromoethyl)phosphonate (1) (0.45 ml, 2.5 mmol), 2-ethoxyethylamine (0.26 ml, 2.5 mmol), K2CO3 (0.346 g, 2.5 mmol) and acetonitrile (10 ml) were added. The mixture was maintained at 70° C. by means of an oil bath for 3 hours under stirring. After cooling the mixture was filtered (G3 frit), and washed with acetonitrile (2*3 ml). The solvent was totally removed by rotoevaporation giving a yellow oil. (31P{1H} NMR in CDCl3 showed two signals of ca. equal intensity at 31.2 and 18.0 ppm, corresponding to the mono-substituted intermediate 2 and a stoichiometric excess the vinyl derivative intermediate 3, respectively). The yellow oil 0.70 ml recovered above was added to a 2 ml vial along with LiClO4 (133 mg, 1.25 mmol). The vial was degassed with dinitrogen, and then quickly and tightly closed. The vial was deepen for 7 hours at 75° C. in an oil bath. The resulting yellow oil was taken up with CHCl3 (3*2 ml), then was treated in a separator funnel with H2O (6 ml) and the lower organic layer was recovered. The water phase was treated again with CHCl3 (3 ml). The combined organic phases were finally concentrated with a dinitrogen stream and then under vacuum pump (to discharge the excess of unreacted 3). A viscous yellow oil was obtained (yield 85%). 1H NMR (CDCl3): δ(ppm)=4.12-4.04 (m, 8H); 3.50-3.46 (m, 4H); 2.84-2.78 (m, 4H); 2.66-2.62 (t, 2H); 1.98-1.87 (m, 4H); 1.35-1.29 (t, 12H); 1.21-1.16 (t, 3H). 31P NMR (CDCl3): δ(ppm)=31.3. | |
With potassium carbonate In acetonitrile at 70℃; for 3h; | 1.ii (ii) Synthesis of N, N-bis [ (diethyl 2 phosphono) ethyl] ethoxyethylamine (4 ); In a 50 mL two-necked round bottom flask equipped with an automatic stirrer and heater, and with a condenser, diethyl (2-bromoethyl) phosphonate (1) (0.45 ml, 2.5 mmol) , 2-ethoxyethylamine (0.26 ml, 2.5 mmol) , K2CO3 (0.346 g, 2.5 mmol) and acetonitrile (10 ml) were added. The mixture was maintained at 70 °C by means of an oil bath for 3 hours under stirring. After cooling the mixture was filtered (G3 frit) , and washed with acetonitrile (2 x 3 ml) . The solvent was totally removed by rotoevaporation giving a yellow oil. (31P{1H} NMR in CDC13 showed two signals of ca . equal intensity at 31.2 and 18.0 ppm, corresponding to the mono-substituted intermediate 2 and a stoichiometric excess the vinyl derivative intermediate 3, respectively) .The yellow oil 0.70 ml recovered above was added to a 2 ml vial along with LiClO4 (133 mg, 1.25 mmol). The vial was degassed with dinitrogen, and then quickly and tightly closed. The vial was deepen for 7 hours at 75°C in an oil bath. The resulting yellow oil was taken up with CHC13 (3 x 2ml), then was treated in a separator funnel with H2O (6 ml) and the lower organic layer was recovered. The water phase was treated again with CHC13 (3 ml). The combined organic phases were finally concentrated with a dinitrogen stream and then under vacuum pump (to discharge the excess of unreacted 3). A viscous yellow oil was obtained (yield 85%) .IH NMR (CDC13) : δ(ppm) = 4.12-4.04 (m, 8H); 3.50-3.46 (m, 4H); 2.84-2.78 (m, 4H); 2.66-2.62 (t, 2H); 1.98- 1.87 (m, 4H); 1.35-1.29 (t, 12H); 1.21-1.16 (t, 3H). 31P NMR (CDC13): δ(ppm) = 31.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: diethyl 2-bromoethylphosphonate; 2-methoxyethylamine In water for 3h; Heating / reflux; Stage #2: With sodium hydroxide In water | 3.i Example 3; Synthesis of bis [ (dimethoxyethylphosphino) ethyl] methoxyethylamine (PNPlO); (i) Synthesis of N- (diethyl 2-phosphono) ethyl ethoxyethylamine (2') In a 25 ml two-necked round bottom flask was placed diethyl (2-bromoethyl ) phosphonate (1) (2.45g, O.Olmol). Water (2 ml) and 2-methoxyethylamine (6 ml, 0.07mol) were added. Additional water (4 ml) was added and the mixture was refluxed for 3 hours. After cooling the mixture was colourless and viscous. NaOH 10% (5 ml) was added and then the mixture was reduced in volume by roto-evaporation to remove the excess of unreacted amine and water. The viscous residue was treated with diethylether (3 x 30 ml) under vigorous stirring. The combined ethereal phases were treated with Na2SO4 (ca. 500mg) , filtered and concentrated by a gentle nitrogen stream and the residue dried under vacuum pump (yield 55%) . IH NMR (CDC13) : δ(ppm) = 4.09 (m, 4H), 3.48 (t, 2H),3.34 (s, 3H), 2.92 (m, 2H), 2.79 (t, 2H), 1.99 (m, 2H),1.31 (t, 6H) .31P{1H} (CDC13) : δ(ppm) = 31.1. |
With potassium carbonate In acetonitrile at 65℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; dichloromethane; benzene | 37 Example 37 Example 37 A solution of diol 67 (50 mg, 0.118 mmol) in CH2Cl2 (5 mL) was treated with diethyl (2-bromoethyl)-phosphonate (64 μL, 0.354 mmol) and Ag2CO3 (65 mg, 0.236 mmol). After the reaction mixture was stirred for 3 d at 40° C., additional phosphonate (64 μL, 0.354 mmol), Ag2CO3 (65 mg, 0.236 mmol), and benzene (5 mL) were introduced. After the reaction mixture was stirred for another 4 days at 70° C., the mixture was filtered through a medium-fritted funnel. The crude product was chromatographed by silica gel (eluding 4-5% MeOH/CH2Cl2) to give diethylphosphonate 74 (8 mg, 12%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ7.81 (bs, 1H), 7.17 (dd, 1H), 7.03 (t, 1H), 6.60 (d, 2H), 6.52 (d, 2H), 5.25 (s, 2H), 5.15 (s, 2H), 4.71 (bs, 2H), 4.47 (m, 2H), 4.14 (m, 4H), 3.12 (m, 1H), 2.27 (m, 2H), 1.34 (t, 6H), 1.27 (d, 6H). 31P NMR (300 MHz, CDCl3) δ28.0. | |
In methanol; dichloromethane; benzene | X.34 Example X34 Example X34 A solution of diol 67 (50 mg, 0.118 mmol) in CH2Cl2 (5 mL) was treated with diethyl (2-bromoethyl)-phosphonate (64 mL, 0.354 mmol) and Ag2CO3 (65 mg, 0.236 mmol). After the reaction mixture was stirred for 3 d at 40° C., additional phosphonate (64 μL, 0.354 mmol), Ag2CO3 (65 mg, 0.236 mmol), and benzene (5 mL) were introduced. After the reaction mixture was stirred for another 4 days at 70° C., the mixture was filtered through a medium-fritted funnel. The crude product was chromatographed by silica gel (eluding 4-5% MeOH/CH2Cl2) to give diethylphosphonate 74 (8 mg, 12%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.81 (bs, 1H), 7.17 (dd, 1H), 7.03 (t, 1H), 6.60 (d, 2H), 6.52 (d, 2H), 5.25 (s, 2H), 5.15 (s, 2H), 4.71 (bs, 2H), 4.47 (m, 2H), 4.14 (m, 4H), 3.12 (m, 1H), 2.27 (m, 2H), 1.34 (t, 6H), 1.27 (d, 6H). 31P NMR (300 MHz, CDCl3) δ 28.0. |
Yield | Reaction Conditions | Operation in experiment |
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65% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
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60% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
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91% | With sodium carbonate In ethanol for 18h; Heating / reflux; | 53.1 Stage 1: Diethyl [(4-tert-butoxycarboxylaminopiperidin-1-yl)ethyl]phosphonate: A mixture containing 4 g of piperidin-4-ylcarbamic acid tert-butyl ester, 5.38 g of diethyl 2-bromoethylphosphonate, 3.2 g of sodium carbonate in 50 ml of ethanol is heated under reflux for 18 hours. After cooling the reaction medium, the solid is filtered and the filtrate is concentrated under vacuum. After purification on a silica column (dichloromethane-methanol: 90-10), 6.6 g of diethyl [(4-tert-butoxycarboxylaminopiperidin-1-yl)ethyl]phosphonate with a yield of 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 53% 2: 32% | With sodium azide In N,N-dimethyl-formamide at 120℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
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70% | Stage #1: (S)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine With n-butyllithium In tetrahydrofuran; n-heptane at -78℃; Inert atmosphere; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran; n-heptane at -78℃; Inert atmosphere; | 1 Production of (2R,5S)-2-(2-(diethoxy-phosphoryl)ethyl)-2,5-dihydro-3,6-dimethoxy-5-isopropyl pyrazine Example 1 Production of (2R,5S)-2-(2-(diethoxy-phosphoryl)ethyl)-2,5-dihydro-3,6-dimethoxy-5-isopropyl pyrazine 0.52 mol of (S)-2,5-dihydro-3,6-dimethoxy-2-isopropyl pyrazine are solved in 400 ml of absolute THF under argon and are cooled to -78° C. Under stirring, 200 ml of a 2.7 M solution of butyl lithium (in heptane) (0.54 mol) are added in drops and slowly. Subse-quently, a solution of 0.52 mol of diethyl-(2-bromoethyl) phosphonate in 300 ml of absolute THF is added in drops and slowly during stirring, and the mixture is stirred for further 3 h at -78° C. Then, 11.7 ml (about 0.2 mol) anhydrous acetic acid are added slowly. The reaction mixture is allowed to warm up slowly to room temperature. The solvent is removed, and the residue is solved in 600 ml of diethyl ether and washed with 200 ml of water. The aqueous phase is still extracted three times with each 100 ml of diethyl ether. The combined ether phases are dried over MgSO4, filtered and the solvent is removed in vacuo. The residue is solved in a mixture of diethyl ether and hexane (1:10) and filtered over a bed of silica gel. Thereby, first it is eluted with diethyl ether and hexane (1:5). Yield: about 70% of a yellow liquid. 1H-NMR (CDCl3): 0.71, 1.04 (d, 6H, CH(CH3)2), 1.33 (t, 6H, P(O)(OCH2CH3)2), 1.68-2.25 (m, 4H, CHCH2CH2P), 3.65, 3.67 (s, 6H, OCH3), 4.02 (m, 1H), 4.10-4.20 (m, 4H, P(O)(OCH2CH3)2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | at 50℃; for 21h; Inert atmosphere; | |
89% | at 50℃; for 21h; | |
58% | In acetone at 50℃; | 2.2.1. Preparation of 1,4-bis[((N-phosphono-2-ethyl)-4,4'-bipyridinium)-methyl]benzene tetrachloride (PBT) The synthesis route of compound PBT was performed following sequential process reported by Taya, M. group [25]. First, 1-diethylethylphosphonate-4,4'-bipyridinium bromide (1) was prepared by mixing 4,4'-bipyridine (2 g, 12.8 mmol) and diethyl bromoethylphosphonate (3.14 g, 12.8 mmol) in acetone (20 ml) in a 100 ml round bottomed flask and heated under stirring at 50 °C until thesolid precipitate was formed. The precipitate was filtered. The filtrate was heated again and the process was repeated until no more solid formed. The as-obtained precipitate was washed with ether and dried under vacuum to pale yellow product (3 g, 58%). Then, 1,4-bis[((N-diethylphosphono-2-ethyl)-4,4'-bipyridinium)methyl]benzene tetrabromide (2) was prepared by mixing the above product (2 g, 4.99 mmol) and 1,4-bis(bromomethyl) benzene (0.657 g, 2.49 mmol) in acetonitrile (50 ml) in a 100 ml round bottomed flask and refluxed under stirring for 24 h. The resultingprecipitatewas filtered and washed with ether and hot acetonitrile,then dried under vacuum to yield 2.2 g of yellow product. Finally,1,4-bis[((N-Phosphono-2-ethyl)-4,40-bipyridinium)-methyl]-benzenetetrachloride (3) was obtained by adding the above product (2 g, 1.88 mmol) to hydrochloric acid solution (40 ml) and allowed to reflux for 24 h under stirring. The solvent was removed under vacuum and the compound was crystallized with ethanol, filtered and dried in the vacuum to yield 1.7 g of pale yellow product. |
45% | In acetone at 50℃; | |
44% | In acetonitrile for 72h; Reflux; | 3 synthesis of compound 3 The 10.0g of 4,4 '-bipyridine and 13.1g the 2-bromo ethyl diethyl phosphoric acid in 50 ml acetonitrile to three days of reflux. Subsequently, filtering out pale yellow residue. Furthermore, in 200 ml of acetone and stirring the resulting pale yellow solid is filtered. Repeat the above procedure 3 times. Furthermore, filtering out which precipitates out of the solution and washing several times with acetone. Furthermore, in the oven 70 °C dry the product in order to obtain compound 3. The yield is 44%. |
at 20℃; for 12h; | 1 3.12 g of 4,4'-Dipyridyl was mixed with 5.10 g of bisethyl-2-bromoethyl phosphonate and the mixture was reacted for 12 hours at room temperature. 300 ml of cold diethylether was added thereto, followed by stirring for additional 1 hour and filtration of precipitate. The precipitate was washed with 50 ml of diethylether three times and dried under vacuum to obtain 6.21 g of compound (IV). | |
In acetone at 45℃; | 1 4,4'-bipyridine (6 g, 0.04 mol), Diethyl 2-bromoethylphosphonate (10.0 g, 0.045 mol), 50ml acetone was added 150ml round bottom flask, Install the condenser, Reaction at 45 ° C. After a period of reaction, Bottom of the bottom of the flask with a cationic salt precipitation, Continue heating the reaction until no more precipitate is formed. The resulting precipitate was filtered, Washed several times with anhydrous ether, Vacuum drying oven, A pure yellow solid was obtained, It is compound 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 20℃; Reflux; | 29.1 A mixture of 4-amino-1-benzylpiperidine (5 g) and (2-bromoethyl)phosphonic acid diethyl ester (7 g) is brought to reflux in EtOH (50 ml). After stirring at AT for 18 hours, the solid is filtered off and, after concentration, chromatography (Al2O3) is performed, elution being carried out with DCM/MeOH (v/v; 85/15) and 62 g of expected product are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: diethyl 2-bromoethylphosphonate; 2-methoxyethylamine In water for 3h; Reflux; Stage #2: With sodium hydroxide In water | 3.i In a 25 ml two-necked round bottom flask was placed diethyl (2-bromoethyl)phosphonate (1) (2.45 g, 0.01 mol). Water (2 ml) and 2-methoxyethylamine (6 ml, 0.07 mol) were added. Additional water (4 ml) was added and the mixture was refluxed for 3 hours. After cooling the mixture was colourless and viscous. NaOH 10% (5 ml) was added and then the mixture was reduced in volume by roto-evaporation to remove the excess of unreacted amine and water. The viscous residue was treated with diethylether (3×30 ml) under vigorous stirring. The combined ethereal phases were treated with Na2SO4 (ca. 500 mg), filtered and concentrated by a gentle nitrogen stream and the residue dried under vacuum pump (yield 55%).1H NMR (CDCl3): δ(ppm)=4.09 (m, 4H), 3.48 (t, 2H), 3.34 (s, 3H), 2.92 (m, 2H), 2.79 (t, 2H), 1.99 (m, 2H), 1.31 (t, 6H).31P{1H} (CDCl3): δ(ppm)=31.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 20℃; | II.20 To a solution of the derivative obtained in Synthesis Example 10 in DMF was added Cs2CO3 (4.6598 mmol), and the reaction mixture was left at room temperature for 30 min for reaction. To this mixture was slowly added bromo ethylphosphonate (2.1435 mmol), followed by stirring at room temperature for 18 hours. Extraction with ethyl acetate and water gave an organic phase which was then dried over Na2SO4 and concentrated under vacuum. Purification through column chromatography using methanol/methylene chloride afforded the desired product. Examples of the product are given in Table 5, below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: ethane-1,2-dithiol With sodium hydride In tetrahydrofuran for 0.166667h; Stage #2: diethyl 2-bromoethylphosphonate In tetrahydrofuran for 2h; | |
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 49.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 5.22. 2',3'-O-Isopropylideneadenosine-8-thioethylenephosphonic acid (48) To a suspension of K2CO3 (140 mg, 1.02 mmol) in DMF (2 mL) 2',3'-O-isopropylidene-8-mercaptoadenosine (46) (prepared from 45 as described24 (288 mg, 0.85 mmol) was added followed by diethyl 2-bromoethylphopsphonate (187 mg, 1.02 mmol). The mixture was stirred overnight at rt, evaporated, dissolved in EtOAc (100 mL), washed with H2O, dried, and evaporated to give intermediate 47 as a foam. 1H NMR (CDCl3) δ 8.23 (s, 1H), 6.55 (dd, J = 11.81, 1.27 Hz, 1H), 5.95 (d, J = 5.27 Hz, 1H), 5.53 (s, 2H), 5.21 (t, J = 5.46 Hz, 1H), 5.06 (dd, J = 5.62, 0.60 Hz, 1H), 4.51 (s, 1H), 4.20-4.07 (m, 4H), 3.98-3.93 (m, 1H), 3.77 (dt, J = 12.89, 1.68 Hz, 1H), 3.59-3.41 (m, 2H), 2.34 (ddd, J = 18.31, 8.58, 7.73 Hz, 2H), 1.67 (s, 3H), 1.37 (s, 3H), 1.35 (t, J = 7.08 Hz, 6H). To a solution of 47 (0.428 g, 0.85 mmol) in dry MeCN (10 mL) 2,6-lutidine (0.5 mL, 4.25 mmol) was added followed by TMS-Br (0.572 mL, 4.25 mmol). The mixture was stirred overnight at rt, evaporated, diluted with EtOH and evaporated again. The crude product was purified by preparative HPLC with 70% MeCN/0.1 M TEAB (25-50 linear gradient) to give 48 as a foam (360 mg, 77% triethylammonium salt). 1H NMR (D2O) δ 8.10 (s, 1H), 6.22-6.13 (m, 1H), 5.48-5.40 (m, 1H), 5.18-5.08 (m, 1H), 4.47-4.38 (m, 1H), 3.88 (dd, J = 12.51, 3.49 Hz, 1H), 3.83 (dd, J = 12.48, 4.75 Hz, 1H), 3.53-3.40 (m, 1H), 3.21 (q, J = 7.33 Hz, 4H), 2.04 (td, J = 17.01, 8.46 Hz, 2H), 1.70 (s, 3H), 1.45 (s, 3H), 1.30 (t, J = 7.33 Hz, 6H)). 31P NMR (D2O) δ 20.57 (s). HRMS calcd for C15H21N5O7PS 446.0905 (M-H)-, found 446.0979. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium methylate In methanol at -20℃; Inert atmosphere; | 5.20. 2',3'-O-Isopropylideneadenosine-5'-thioethylenephosphonic acid (43) 2',3'-O-Isopropylidene-5'-S-acetyladenosine (41, 0.5 g, 1.37 mmol)25 was dissolved in MeOH (10 mL), the solution was degassed with Ar, cooled to -20 °C, and diethyl 2-bromoethylphosphonate (380 μL, 2.05 mmol) was added followed by MeONa (165 mg). The mixture was stirred overnight, evaporated, dissolved in EtOAc (100 mL), washed with H2O, dried over MgSO4, filtered, and evaporated to give the intermediate 42 as a foam (0.53 g, 79%). 1H NMR (CDCl3) δ 8.35 (s, 1H), 7.90 (s, 1H), 6.06 (d, J = 2.10 Hz, 1H), 5.74 (s, 2H), 5.50 (dd, J = 6.40, 2.11 Hz, 1H), 5.06 (dd, J = 6.39, 3.32 Hz, 1H), 4.40-4.34 (m, 1H), 2.89 (dd, J = 13.68, 7.41 Hz, 1H), 2.81 (dd, J = 13.70, 6.32 Hz, 1H), 2.78-2.72 (m, 2H), 2.02-1.94 (m, 2H), 1.63-1.59 (m, 3H), 1.39 (s, 3H), 1.29 (dt, J = 7.06, 2.27 Hz, 6H). 31P NMR (CDCl3) δ 29.21 (s). To the solution of 42 (0.52 g, 1.08 mmol) in dry MeCN (10 mL) 2,6-lutidine (0.64 mL, 5.4 mmol) was added followed by TMS-Br (0.73 mL, 5.4 mmol). The mixture was stirred overnight at rt, evaporated, diluted with EtOH, and evaporated. The crude product was purified by preparative HPLC with 70% MeCN/0.1 M TEAB (25-50 linear gradient) to give 43 (410 mg, 71% triethylammonium salt). 1H NMR (D2O) δ 8.36 (s, 1H), 8.29 (s, 1H), 6.30 (d, J = 2.79 Hz, 1H), 5.62 (dd, J = 6.48, 2.82 Hz, 1H), 5.18 (dd, J = 6.49, 3.10 Hz, 1H), 4.56 (dt, J = 6.91, 3.10 Hz, 1H), 3.25 (q, J = 7.34 Hz, 6H), 2.92 (d, J = 6.72 Hz, 1H), 2.77 (dd, J = 15.41, 7.48 Hz, 2H), 1.90-1.82 (m, 2H), 1.71 (s, 3H), 1.49 (s, 3H), 1.33 (t, J = 7.33, Hz, 9H). 31P NMR (D2O) δ 22.61 (s). HRMS calcd for C15H21N5O6PS 430.0956 (M-H)-, found 430.0983. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: diethyl 2-bromoethylphosphonate; [(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]methyl}amine With potassium carbonate In N,N-dimethyl-formamide at 90℃; Stage #2: trifluoroacetic acid | 34 To a solution [(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1 ,1 -dioxido-5-phenyl- 2,3,4,5-tetrahydro-1 ,4-benzothiazepin-8-yl]methyl}amine (50 mg, 0.120 mmol) in DMF (4 mL) was added potassium carbonate (49.8 mg, 0.360 mmol) and diethyl (2- bromoethyl)phosphonate (17.65 mg, 0.072 mmol). The reaction mixture was heated at 90°C overnight, cooled to room temperature, and concentrated under reduced pressure. To the residue was added trifluoroacetic acid, and the solution was concentrated under reduced pressure. Purification by RP-HPLC (MeCN/H2O with 0.05% TFA) afforded the title product (34 mg, 95%, TFA salt) as a white solid: 1 H NMR (MeOH-d4) δ ppm 8.04 (s, 1 H), 7.27 - 7.59 (m, 5H), 6.38 (s, 1 H), 6.04 - 6.21 (m, 2H), 3.88 - 4.24 (m, 4H), 3.50 - 3.68 (m, 4H), 3.16 - 3.35 (m, 3H), 2.20 - 2.49 (m, 1 H), 1 .78 - 1 .95 (m, 1 H), 1 .60 - 1 .75 (m, 1 H), 1 .41 - 1 .58 (m, 1 H), 1 .01 - 1 .36 (m, 7H), 0.89 (t, J = 7.6 Hz, 3H), 0.81 (t, J = 6.8 Hz, 3H); ES-LCMS m/z 553 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: diethyl 2-bromoethylphosphonate; 1-Phenyl-1H-tetrazole-5-thiol With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide for 12h; Inert atmosphere; Stage #2: With ammonium molybdate; water; dihydrogen peroxide In ethanol for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 2,6-di-tert-butyl-pyridine; copper(l) chloride In dichloromethane at 40℃; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 2,6-di-tert-butyl-pyridine; copper(l) chloride In dichloromethane at 40℃; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.02% | With sodium hydride In dimethyl sulfoxide at 60℃; for 20h; Inert atmosphere; | 2.2. Synthesis of (2-(9H-carbazol-9-yl)ethyl)phosphonic acid To carbazole (1.86 g, 11.13 mmol) in dry DMSO (20 mL) NaH(0.49 g, 12.24 mmol) was added, and the solution was stirred for0.5 h at room temperature under N2. Then, diethyl (2-bromoethyl)phosphonate (2.64 g, 12.24 mmol) was added and the mixture was heated at 60 C for 20 h. The reaction mixture waspoured into water (100 mL), acidified with 1 M hydrochloric acidand then extracted with ethyl acetate (3 100 mL). The combinedorganic extracts were washed with brine, dried with magnesiumsulfate and the solvent was removed. The residue was dissolvedin a minimum amount of ethyl acetate and chromatographicseparation on silica was achieved by eluting with pet. ether:ethylacetate (2:1). The solvent was removed under reduced pressure togive diethyl(2-(9H-carbazol-9-yl)ethyl)phosphonate as pale yellowliquid (1.37 g, 37.02%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate In ethanol at 20℃; for 2h; | Synthesis of ω-hydrazinoalkylphosphonic acids 1a-c; general procedure General procedure: To a solution of N2H4·H2O (20.00g, 0.40mol) in EtOH (12mL) was added ω-haloalkylphosphonate (0.020mol) and the resultant solution was stirred at room temperature (time given in Table 1). Unreacted hydrazine hydrate was distilled under reduced pressure. The residue was then treated with NaOH/H2O solution (2.0M, 20.0mL, entries 1, 3, and 4; 40.0mL, entry 2) and stirred at rt (time given in Table 1). After evaporation, the residue was dissolved in H2O (50mL) and evaporated (this operation was repeated three times to remove any remaining traces of hydrazine hydrate). Then 6N HCl (aq) (entries 1, 3, and 4) or concd HCl (entry 2) (50mL) was added, and the mixture heated at reflux (time given in Table 1) and evaporated. In two cases (entries 1 and 3) after evaporation of HCl, the residue was additionally treated with concd HCl (aq) solution (30mL), stirred at rt for 12h, filtered, and evaporated. The residue was dissolved in MeOH/H2O (5:2, 35mL, entry 1), or MeOH (30mL, entry 2; 25mL, entries 3 and 4), filtered (entry 2), treated with propylene oxide (3mL), and left in a refrigerator for 24h. The crude products were separated by filtration (entries 1 and 2) or by decantation (entries 3 and 4) and washed with MeOH (2×5mL). The crude hydrazinophosphonic acids 1a,b (entries 1 and 2) were dissolved in boiling H2O (10mL, entry 1; 21mL, entry 2) and boiling MeOH/H2O (4:1, 16mL, entry 1; 53mL, entry 2) was added, and after cooling, the pure crystalline products were obtained. In the case of hydrazinophosphonic acid 1c (entries 3 and 4) the crude product was dissolved in H2O (20mL) and activated carbon (0.1g) was added. The mixture was stirred at room temperature (3h), filtered, and the filtrate was evaporated to give 1c (2.66g, 86%, entry 3; 2.24g, 73%, entry 4) as an oil that required the hydrazone-mediated purification procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: C27H26N4O2 With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 2h; Inert atmosphere; Stage #2: diethyl 2-bromoethylphosphonate In dimethyl sulfoxide; mineral oil for 20h; Inert atmosphere; | A71 Preparation of Co. 68 Preparation of Co. 68 NaH 60% (27.4 mg, 0.68 mmol) was added to Co. 1 (0.2 g, 0.46 mmol) in DMSO (2.8 mL) at r.t. under N2. The mixture was stirred for 2h then dicthyl-2- bromoethylphosphonatc (0.13 mL, 0.68 mmol ) was added and the r.m. was stirred for 20h. The mixture was poured into water, K2C03 was added and extracted with EtOAc. The organic layer was evaporated until dryness. The residue was taken up with EtOAc and water. The organic layer was extracted, dried over MgS04, filtered and evaporated. The residue (0.27 g) was purified by prep. LC (25g of irregular SiOH 35-40μιη GraceResolv, mobile phase gradient from 100% DCM to 95% DCM 5% MeOH 0.1% NH4OH). The pure fractions were collected and evaporated to give 0.2g which was crystallized from DIPE, filtered and dried to give 137 mg of Co. 68 (50%). m.p.: 90°C (dsc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride In dimethyl sulfoxide at 60℃; for 6h; Inert atmosphere; | To 9-methylfluorene (3.6 g, 20 mmol) in dry DMSO (40 mL), NaH (60%, 0.48 g, 20 mmol) wasadded slowly in a N2 atmosphere. Then, diethyl (2-bromoethyl)phosphonate(5.0 g, 20.4 mmol) was addedinto the reaction, and then mixture was heated at 60 oC for 6 h. Theresulted mixture was poured into water (50 mL), which was extracted with ethylacetate (3×40 mL). The organic phase was washed with brine, and dried withmagnesium sulfate and the solvent was removed under vacuum. The residue wasdissolved in a minimum amount of ethyl acetate and chromatographic separationon silica was achieved by eluting with pet. ether:ethyl acetate (2:1). Thesolvent was removed under reduced pressure to give(2-(9-methyl-9H-fluoren-9-yl)ethyl)phosphonate as pale yellow liquid (5 g, 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 3-Aminomethylpyridine; carbon disulfide With triethylamine In water for 0.0833333h; Stage #2: diethyl 2-bromoethylphosphonate In water at 20℃; for 2h; | 1 General procedure for the synthesis of compounds 17a-17i General procedure: To a mixture of pyridin-3-ylmethanamine 18 (108 mg, 1 mmol),TEA (100 mg, 1 mmol) in water (10 mL), CS2 (91 mg, 1.2 mmol) was added dropwise. After stirring for 5 min, the corresponding halide19 (1 mmol) or Michael acceptor 20 (1 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then extracted with ethyl acetate (30 mL 3). The organic phase was combined and dried over Na2SO4, concentrated under vacuum and purified by column chromatography on silica gel or recrystallization (ethyl acetate/petroleum ether) to afford the corresponding compound 17 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at 20℃; Inert atmosphere; | SYNTHESIZE HYDROLYTICALLY STABLE COUPLING AGENT The new coupling agent vinyl glycidyl ethylphosphonic acid (FIG. 9) was synthesized according to the phosphorylation method for compound 10. This agent has a phosphonic group, which can strongly bind with FA and teeth. Only ether moieties instead of esters existing in the entire molecule make it hydrolytically stable. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | at 80℃; for 1h; Microwave irradiation; | 27 Example 27 1-n-hexyl-2-butylimidazole (20.8 g, 0.1 mol)2-bromoethylphosphonic acid diethyl ester (27.0 g, 0.11 mol),In a two-neck round bottom flask,Into a microwave reactor,Magnetic stirring,The temperature was set at 80 ° C,Power is 280W,Microwave continuous radiation reaction 60min,Condensation during the reaction reflux,After the end of the reaction, the product was washed with ethyl acetate four to five times to remove the unreacted starting material,Then vacuum dried at 80 for 3h,Yielding a light yellow viscous liquid 1-n-hexyl-2-butyl-3- (2-phosphonic acid diethyl ester) ethylimidazolium bromide34.0 g, 75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at 100℃; for 1.66667h; Microwave irradiation; | 26 Example 26 1-methylimidazole (8.2 g, 0.1 mol), respectively,2-bromoethylphosphonic acid diethyl ester (27.0 g, 0.11 mol),In a two-neck round bottom flask,Into a microwave reactor,Magnetic stirring,The temperature was set at 100 ° C,Power is 400W,Microwave continuous radiation reaction 100min,Condensation during the reaction reflux,After the end of the reaction, the product was washed four to five times with ethyl acetate to remove the unreacted starting material and then vacuum dried at 80 ° C for 3 h,To give a pale yellow viscous liquid 1-methyl-3- (2-phosphonic acid diethyl ester) ethylimidazolium bromide26.2 g, 80% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With toluene at 100℃; for 1.66667h; Microwave irradiation; | 16 Triphenylphosphine (26.2 g, 0.1 mol), diethyl 2-bromoethylphosphonate (27.0 g, 0.11 mol), followed byWas added into a two-necked round-bottom flask, 180 mL of toluene was added, placed in a microwave reactor, magnetically stirred, and the temperature was set to100 , the power of 450W, microwave continuous radiation reaction 100min, the reaction process condensed reflux, after the end of the reactionThe product was washed with toluene four to five times to remove unreacted starting material and then dried in vacuo at 80 ° C for 3 h to give a colorless viscousLiquid (2-phosphonic acid diethyl ester) ethyltriphenylphosphonium bromide, 35.5 g, was obtained in a yield of 70% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In toluene at 80℃; for 1h; Microwave irradiation; | 19 Were taken 2-methylpyridine (9.3g, 0.1mol), 2- bromoethyl phosphonate diethylester (27.0g, 0.11mol), followed by adding two-necked round bottom flask was added 180mLof toluene, into a microwave reactor, with magnetic stirring, the temperature set at 80, power of 350W, continuous microwave radiation reaction 60min, during refluxcondensation reaction, after the reaction product was washed with toluene four to fivetimes to remove unreacted starting materials, then 80 and dried in vacuo 3h, to givea pale yellow viscous liquid of 1- (2-diethyl) ethyl-2-methylpyridine bromide 18.9g, 56%yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In toluene at 90℃; for 1.33333h; Microwave irradiation; | 20 Were taken 3-methylpyridine (9.3g, 0.1mol), 2- bromoethyl phosphonate diethylester (27.0g, 0.11mol), followed by adding two-necked round bottom flask was added 180mLof toluene, into a microwave reactor, with magnetic stirring, the temperature set at 90, power of 400W, continuous microwave radiation reaction 80min, during refluxcondensation reaction, after the reaction product was washed with toluene four to fivetimes to remove unreacted starting materials, then 80 and dried in vacuo 3h, to givea pale yellow viscous liquid of 1- (2-diethyl) ethyl-3-methyl-pyridine bromide 23.0g,68% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In toluene at 80℃; for 1h; Microwave irradiation; | 21 Were taken 3-ethyl pyridine (10.7g, 0.1mol), 2- bromoethyl phosphonate diethylester (27.0g, 0.11mol), followed by adding two-necked round bottom flask was added 180mLof toluene, into a microwave reactor, with magnetic stirring, the temperature set at 80, power of 350W, continuous microwave radiation reaction 60min, during refluxcondensation reaction, after the reaction product was washed with toluene four to fivetimes to remove unreacted starting materials, then 80 and dried in vacuo 3h, to givea pale yellow viscous liquid of 1- (2-diethyl) pyridin-ethyl-3-ethyl bromide 19.7g, 56%yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydroxide; potassium hydroxide In dimethyl sulfoxide at 20℃; for 4h; | 1.D Step D - Synthesis of Compound Id Step D - Synthesis of Compound Id A solution of Compound lc (1000 mg, 3.66 mmol) in dioxane (5.0 mL) was treated at room temperature with 3-oxotetrahydrofuran (1260 mg, 14.64 mmol) and AcOH (0.050 mL). The reaction mixture was capped and stirred at room temperature for 24 hours. The reaction mixture was directly applied to a dry 80g silica gel column. Gradient elution with 0 to 30% MeOH/ dichloromethane provided the intermediate that was taken up in DMSO (6 mL) and treated with diethyl 2-bromoethylphosphonate (1.330 ml, 7.32 mmol), tetrabutylammonium hydroxide triacontahydrate (585 mg, 0.732 mmol) and potassium hydroxide (616 mg, 10.98 mmol). The reaction mixture was allowed to stir at room temperature for 4 hours, neutralized with glacial acetic acid and directly purified using RP-MPLC to provide Compound Id which was used without further purification. Mass Calc'd for C24H32N3O7P: 505.1, found 506.1 (M+H)+; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-amino-3-(benzyloxy)-N-methyl-4-oxo-1,4-dihydropyridine-2-carboxamide; cyclopentanone With acetic acid In 1,4-dioxane at 20℃; for 16h; Stage #2: diethyl 2-bromoethylphosphonate With tetrabutylammonium hydroxide triacontahydrate; potassium hydroxide In dimethyl sulfoxide at 20℃; for 3h; | 1.D Step D - Synthesis of Intermediate Compound Id A solution of intermediate lc (2.00 g, 7.32 mmol) in dioxane (20.0 mL) was treated at room temperature with cyclopentanone (3.24 ml, 36.6 mmol) and glacial acetic acid (0.050 mL). The reaction mixture was allowed to stir at room temperature for 16 hours and then directly applied to a dry prepacked silica gel column. Purification by column chromatography on silica gel (0 to 30% MeOH/ dichloromethane) provided an intermediate compound. This intermediate compound was taken up in DMSO (20 mL) and treated with diethyl 2- bromoethylphosphonate (2.66 ml, 14.64 mmol), tetrabutylammonium hydroxide, triacontahydrate (0.585 g, 0.732 mmol) and potassium hydroxide (1.232 g, 21.95 mmol). The reaction mixture was allowed to stir at room temperature for 3 hours, neutralized with glacial acetic acid and directly purified using RP-HPLC to provide intermediate compound Id. Mass (calculated) for C25H34N3O6P: 503.2, found 504.5 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at 70℃; for 24h; | 3 Preparation of Compound 3 Description: 50 g (319 mmol, leq) of 4-aminobutyraldehyde diethyl acetal are dissolved at room temperature in 200 ml of THF and 51.5 ml (372 mmol, 1.2 eq) of triethylamine, and then 75.99 g (310 mmol, leq) of diethyl-2-bromethyl phosphonate are added in drops. Next the solution is heated to 70° C. and agitated at this temperature for 24 hours. The solvent is removed on the rotary evaporator. The residue is shaken vigorously with ether and filtered off. The remaining solid is extracted twice more with ether. The ether filtrates are combined and evaporated. The resulting product is a yellow oil, which is used without further purification in the next reaction. (0214) 1H-NMR (DMSO-d6): 4.45 (t, 1H); 3.98 (m, 4H); 3.54 and 3.42 (2m, 2×2H); 2.5-2.8 (m, 4H); 1.90 (m, 2H); 1.25-1.60 (m, 4H); 1.22 (t, 6H); 1.10 (2t, 6H). 31P-NMR (DMSO-d6): 30 ppm. (0215) The intermediate product obtained in the first step is dissolved in 400 ml of THF, mixed with 85.94 ml (620 mmol, 2 eq) of triethylamine and cooled to 0° C. Then 66.11 ml (465 mmol, 1.5 eq) of benzyl chloroformate are added in drops, the cooling is removed and agitation is performed overnight at room temperature. Next the reaction mixture is neutralised with 1 M of hydrochloric acid and the solvent is evaporated off. The residue is shaken with ether and stored overnight in the refrigerator. The resulting solid is separated and thoroughly washed twice more with ether. The ether solutions are combined and evaporated off. The residue is purified by chromatography via a silica gel column. In doing so, initially all impurities are eluted with hexane:acetic ether 2:1 and then the product with acetic ether. (0216) Yield: 85.752 g (60.2%) colourless viscous oil. 1H-NMR (DMSO-d6): 7.34 (m, 5H); 5.07 (s, 2H); 4.44 (m, 1H); 3.94 (m, 4H); 3.6-3.2 (m, 8H); 2.02 (m, 2H); 1.46 (m, 4H); 1.19 (m, 6H); 1.09 (m, 6H). 31P-NMR (DMSO-d6): 28.93 and 28.57 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium thioacetate In N,N-dimethyl acetamide; acetonitrile at 45℃; for 2h; | 7 Example 7: Diethyl (Z)-(2-((4-(K-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-l,2,5- oxadiazol-3-yl)thio)ethyl)phosphonate Diethyl (2-bromoethyl)phosphonate (1 g, 4.08 mmol) and potassium thioacetate(0.56 g, 4.9 mmol) in ACN (5 mL) and DMA (1 mL) were heated to 45°C for 2 h. The reaction was cooled to ambient. To the reaction mixture were added sodium hydroxide (0.2 g, 4.9 mmol) and water (3 mL) and reaction was reheated to 50°C. The reaction was cooled to ambient and diluted with EtOAc. The organics were separated, washed with brine, dried and concentrated to afford diethyl (2-mercaptoethyl)phosphonate. MS: 199.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4,5-dimethylthiazole-2-thiol With potassium carbonate In acetone at 40 - 45℃; for 0.333333h; Stage #2: diethyl 2-bromoethylphosphonate In acetone for 1.05h; Reflux; | III.A.1 1. Synthesis of Compound A: diethyl 2-(4,5-dimethylthiazol-2-ylthio)ethylphosphonate K2CO3 (2.85 g, 0.021 mol, Aldrich, >99%) is added, in one go, to a solution of 4,5-dimethylthiazole-2-thiol (3.00 g, 0.021 mol) in 30 ml of acetone. The reaction medium is stirred at a temperature of between 40 and 45° C. After stirring for 20 minutes, diethyl 2-bromoethylphosphonate (5.00 g, 0.020 mol, Aldrich, 97%) is added over a period of time of 3 minutes. The reaction medium is stirred at reflux for 1 hour and is subsequently slowly cooled (2 hours) down to ambient temperature. The precipitate, formed of the residual salts, is filtered off and washed on the filter with 5 ml of acetone. The filtrate is concentrated under reduced pressure (5-6 mbar, 23° C.) until a constant weight is obtained. A brown oil (5.382 g; 0.017 mol; yield 84%) is obtained. The molar purity is greater than 93% (1H NMR). TLC: Rf=0.5 (SiO2; EtOAc; visualization by UV and I2). NMR Characterization of the product obtained: The chemical shifts obtained by 1H and 13C NMR in d6-DMSO are given in the table below. The calibration is carried out with regard to DMSO (2.44 ppm in 1H, at 39.5 ppm in 13C and the 31P calibration with rs=0; rs: reference spectrum). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: diethyl 2-bromoethylphosphonate With pyridine; trifluoromethylsulfonic anhydride In dichloromethane at 20℃; for 0.166667h; Sealed tube; Stage #2: phenol In dichloromethane at 20℃; for 0.5h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71%; 9% | With potassium carbonate; In N,N-dimethyl-formamide; at 153℃; for 15h; | Potassium carbonate, 5.1 g (37 mmol), was added to a mixture of 1.8 g (7.41 mmol) of diethyl 2-bromoethylphosphonate and 1 g (7.41 mmol) of adenine in 20 mL of DMF. The mixture was refluxed for 15 h, the precipitate of potassium carbonate was filtered off, and the solvent was removed under reduced pressure. The residue was washed with acetone, and the white precipitate was filtered off and dried under reduced pressure (oil pump) until constant weight. Yield 1.6 g (71%), mp >250C. IR spectrum, nu,cm-1: 3143 (NH2), 1699 (C=C), 1029 (P=O). 1H NMRspectrum (DMSO-d6), delta, ppm: 1.24 t (6H, CH3, J =7.1 Hz), 2.55 d.t (2H, CH2, J = 18.2, 7.1 Hz), 4.004.09 m (4H, OCH2), 4.53 d.t (2H, CH2, J = 15.8,7.1 Hz), 8.15 s (1H, Harom), 8.24 s (1H, Harom). 31P NMR spectrum (DMSO-d6): deltaP 27.75 ppm. Mass spectrum: m/z 300.1 [M + H]+. Found, %: C 44.33; H 5.81; N 23.18; P 10.54. C11H18N5O3P. Calculated, %:C 44.15; H 6.06; N 23.40; P 10.35. M 299.3. 9-Ethyl-9H-purin-6-amine (2). The filtrate obtained after separation of compound 1 was left to stand for 12 h. The crystalline solid precipitated therefrom was filtered off and dried under reduced pressure (oil pump) until constant weight. Yield 0.1 g (9%), mp 94-96C. IR spectrum, nu, cm-1: 3270, 3105 (NH2), 1673 (C=C). 1H NMR spectrum (CDCl3), delta, ppm: 1.10 t(3H, CH3, J = 7.4 Hz), 3.67 q (2H, CH2, J = 7.3 Hz),7.48 s (1H, Harom), 7.53 s (1H, Harom). Mass spectrum: m/z 202 [M + K]+. Found, %: C 51.68; H 5.70;N 43.17. C7H9N5. Calculated, %: C 51.52; H 5.56;N 42.92. M 163. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | In N,N-dimethyl-formamide at 90℃; for 24h; | 2.3 Step (3),Compound 5 obtained in the step (2) (596 mg, 2 mmol)Diethyl bromoethyl phosphate (490 mg, 2 mmol) was dissolved in 10 mL DMF.The reaction solution is heated to 90 ° C,After 24 hours of reaction,The solvent is spun on a rotary evaporator.The crude product was purified by column chromatography on alumina.The eluent is a mixture of mass ratio chloroform:methanol=15:1,The resulting yellow oil is the compound 6,Yield 40%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In N,N-dimethyl-formamide at 90℃; for 24h; | 1.2 Step (2),Compound 1 obtained in the step (1) (476 mg, 2 mmol)Diethyl bromoethyl phosphate (490 mg, 2 mmol) was dissolved in 10 mL DMF.Heated to 90 ° C,After 24 hours of reaction,The solvent is spun on a rotary evaporator.The crude product obtained was purified by column chromatography on alumina.The eluent is a mixture of mass ratio chloroform:methanol=15:1,Purification gave a yellow oil, Compound 2 (405 mg), yield 42%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With C27H41N3NiO3(2+)*2Cl(1-); tetra-(n-butyl)ammonium iodide; zinc In acetonitrile at 90℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 2,6-di-tert-butyl-pyridine; copper(I) thiophene-2-carboxylate In dichloromethane at 50℃; Inert atmosphere; Sealed tube; | 3. General procedure for the copper-catalyzed oxygen-alkenylation of dialkyl phosphonates General procedure: CuTC (0.02 mmol, 0.10 equiv), the corresponding alkenyl(aryl)iodonium salt 2 (0.6 mmol, 2 equiv) and a stirring bar were charged in a sealed tube. A solution of phosphonate 1 (0.2 mmol, 1 equiv) in dry dichloromethane (2 ml) and 2,6-di-tert-butylpyridine (0.22 mmol, 1 equiv) was added and the resulting mixture was stirred at 50 °C under an argon atmosphere for 16 h. After this time, the reaction was quenched by addition of saturated aqueous solution of NH4Cl (10 ml) and extracted with CH2Cl (2 × 10 ml). The organic layer was dried over Na2SO4, filtered and solvent was removed under vacuum. The final product was purified by column chromatography on silica gel using n-hexane/AcOEt (1:1) as eluent. 4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium hydride In tetrahydrofuran at 55 - 60℃; regioselective reaction; | Compounds 4a-4d (general procedure). General procedure: A mixtureof triethyl phosphite (0.41 mL, 2.5 mmol) and 1,2-dibromoethane(3a), oxalyl chloride (3b), chloroacetylchloride (3c), or ethyl chloroacetate (3d) (3.5 mmol)was heated under reflux at 150-160°C for 3-5 h.Excess reactants were removed under reduced pressure,a solution of pyranopyrimidine 2 (0.74 g, 2.5 mmol)in THF (25 mL) containing sodium hydride (0.07 g,3 mmol) was added to the residue, and the mixture wasfurther heated at 55-60°C for 10-15 h. After completionof the reaction, the solvent was removed underreduced pressure, and the residue was recrystallizedfrom an appropriate solvent.11-Acetyl-2-ethoxy-10-methyl-12-phenyl-3,4,5,12-tetrahydropyrano[2′,3′:4,5]pyrimido-[1,6-b][1,2,4,5λ5]triazaphosphepin-2-one (4a). Yield69%, pale yellow solid, mp 198-200°C (from aqueousEtOH). IR spectrum ν, cm-1: 3138 (NH), 3066(C-Harom), 2918, 2898 (C-Haliph), 1653 (C=O), 1617(C=N), 1553 (C=C), 1240 (P=O), 1033 (P-O-C).1H NMR spectrum, δ, ppm: 1.13 t (3H, CH3, J =7.2 Hz), 2.17 s (3H, CH3), 2.32 s (3H, CH3), 1.93-1.95 m (2H, CH2P), 3.06 t (2H, J = 9 Hz, CH2N),4.00 q (2H, CH2, J = 7.2 Hz), 5.10 s (1H, 12-H), 5.55 s(1H, NH), 6.73-6.84 m (3H, Harom), 7.52-7.54 m (1H,Harom), 7.61-7.64 m (1H, Harom), 8.21 s (1H, 7-H).13C NMR spectrum, δC, ppm: 14.2 (CH3), 17.1 (CH3),26.8 (CH3), 34.2 (C12), 31.6 d (C3, JPC = 129 Hz), 38.0(C4), 58.8 (CH2), 89.9 (C12a), 119.0 (C11), 125.5 (Cp),126.9 (Co), 128.3 (Cm), 139.8 (Ci), 147.2 (C7), 150.9(C12b), 155.8 (C10), 161.2 (C8a), 187.1 (C=O). 31P NMRspectrum: δP 19.5 ppm. Mass spectrum, m/z: 414 [M]+.Found, %: C 57.81; H 5.43; N 13.33. C20H23N4O4P.Calculated, %: C 57.97; H 5.59; N 13.52. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: benzyl ((2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetic acid salt With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate In N,N-dimethyl-formamide at 50℃; for 2h; | 1.3 Step 3 To (2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetate salt (70 mg, 0.15 mmol) dissolved in DMF (2 mL) was added K2CO3(100 mg, 0.72 mmol) and stirred for 30 min. After adding Diethyl (2-bromoethyl)phosphonate (0.2 mL), the reaction mixture was stirred at 50° C. for 2 h. with the reaction monitored by LCMS. The crude reaction mixture was quenched with water, extracted with EtOAc (2×20 mL) and the crude product dissolved in MeOH. The solution was charged with 10% Pd/C and the reaction mixture stirred under H2 atmosphere for 1 h. The crude reaction mixture was filtered over Celite, washed with MeOH and concentrated in vacuo to yield ((2R,4S)-1-(2-(diethoxyphosphoryl)ethyl)-4-phenylpiperidine-2-carbonyl)-L-alanine. The crude material was used in the next reaction without further purification. | |
Stage #1: benzyl ((2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetic acid salt With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate In N,N-dimethyl-formamide at 50℃; for 2h; Stage #3: With palladium 10% on activated carbon; hydrogen In methanol for 1h; | 30.3 Step 3: To (2R,4S)-4-phenylpiperidine-2-carbonyl)-L-alaninate trifluoroacetate (70 mg, 0.15 mmol) dissolved in DMF (2 mL) was added K2CO3 (100 mg, 0.72 mmol) and stirred for 30 min. To the above mixture, diethyl (2-bromoethyl)phosphonate (0.2 mL) was added and stirred at 50° C. for 2 h. The reaction was monitored by LCMS. The crude reaction mixture was quenched with water and extracted with ethyl acetate (2*20 mL). The crude product was dissolved in MeOH and charged with 10% Pd/C (7 mg) under argon. The reaction was stirred under H2 atmosphere for 1 h. The crude reaction mixture was filtered over Celite washed with methanol and concentrated under vacuum to yield ((2R,4S)-1-(2-(diethoxyphosphoryl)ethyl)-4-phenylpiperidine-2-carbonyl)-L-alanine. The crude material was used in the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With air In N,N-dimethyl-formamide | 3-Alkylthio-substituted 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4] triazolo[4,3-b][1,2,4,5]tetrazines 1 General procedure: Carbon disulfi de (0.132 mL, 2.2 mmol) was added to a suspensionof 6-hydrazino-3-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine(0.412 g, 2.0 mmol) in DMF (5 mL) with stirring. The baseNaHCO3 (0.168 g, 2.0 mmol) was added to the resulting solution.After 2 h, the sulfur crystals precipitated from the solution werefi ltered off , then air was bubbled for 1-2 h, followed by the additionof an alkylating agent (2.0 mmol) (methyl iodide (0.12 mL)for 1a, ethyl bromide (0.15 mL) for 1b, octyl chloride (0.34 mL)for 1c, nonyl chloride (0.37 mL) for 1d, decyl bromide (0.414 mL)for 1e, benzyl chloride (0.23 mL) for 1g, cyclooctyl bromide(0.382 g) for 1h, 2-chloroethanol (0.13 mL) for 1i, 1-chloro-2- methoxyethane (0.18 mL) for 1j, 2-(2-chloroethoxy)-ethanol (0.21 mL) for 1k, 1-(2-bromoethoxy)-2-ethoxyethane(0.394 g) for 1l, 1-chloro-2-ethoxyethane (0.22 mL) for 1m,monochloro acetic acid (0.189 g) for 1n, -chloro-4-fl uoroacetophenone(0.345 g) for 1o, diethyl 2-bromoethylphosphonate(0.490 g) for 1p). The reaction mixture was stirred until the startingtetrazine disappeared (TLC control). The solvent wasevaporated in vacuo, the residue was washed with water. Theproduct was washed with hexane and recrystallized from acetonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
155 mg | Stage #1: N-(tert-butoxycarbonyl)-L-prolinol With potassium-t-butoxide In dichloromethane at 0℃; for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate In dichloromethane at 20℃; | 111 Step 1: tert-Butyl (S)-2-((2-(diethoxyphosphoryl)ethoxy)methyl)pyrrolidine-l-carboxylate. To a vial were added t-BuOK (247 mg, 2.2 mmol, 2.2 eq.) and anhydrous DCM (2.0 mL). The mixture was cooled in an ice bath for 20 min, followed by addition of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (201 mg, 1.0 mmol, 1.0 eq.). After the mixture was stirred at 0 °C for 30 min, diethyl (2-bromoethyl)phosphonate (294 mg, 1.2 mmol, 1.2 eq.) was added and the resultant reaction mixture was stirred at room temperature overnight. After being quenched by addition of ice (5 g), the mixture was diluted with ethyl acetate (30 mL), washed with H2O (2 x 10 mL), brine (10 mL), and dried over Na2SO4. After concentration, the residue was purified by silica gel chromatography to afford the title product (155 mg). |
155 mg | Stage #1: N-(tert-butoxycarbonyl)-L-prolinol With potassium-t-butoxide In dichloromethane at 0℃; for 0.5h; Stage #2: diethyl 2-bromoethylphosphonate In dichloromethane at 20℃; | 111 Step 1: tert-Butyl (S)-2-((2-(diethoxyphosphoryl)ethoxy)methyl)pyrrolidine-l-carboxylate. To a vial were added t-BuOK (247 mg, 2.2 mmol, 2.2 eq.) and anhydrous DCM (2.0 mL). The mixture was cooled in an ice bath for 20 min, followed by addition of tert-butyl (S)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (201 mg, 1.0 mmol, 1.0 eq.). After the mixture was stirred at 0 °C for 30 min, diethyl (2-bromoethyl)phosphonate (294 mg, 1.2 mmol, 1.2 eq.) was added and the resultant reaction mixture was stirred at room temperature overnight. After being quenched by addition of ice (5 g), the mixture was diluted with ethyl acetate (30 mL), washed with H2O (2 x 10 mL), brine (10 mL), and dried over Na2SO4. After concentration, the residue was purified by silica gel chromatography to afford the title product (155 mg). |
Tags: 5324-30-1 synthesis path| 5324-30-1 SDS| 5324-30-1 COA| 5324-30-1 purity| 5324-30-1 application| 5324-30-1 NMR| 5324-30-1 COA| 5324-30-1 structure
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P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
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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