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CAS No. : | 1746-28-7 | MDL No. : | MFCD00045052 |
Formula : | C8H8Br2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | APTDRDYSJZQPPI-UHFFFAOYSA-N |
M.W : | 263.96 | Pubchem ID : | 11010825 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 51.79 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.24 cm/s |
Log Po/w (iLOGP) : | 2.66 |
Log Po/w (XLOGP3) : | 3.76 |
Log Po/w (WLOGP) : | 3.39 |
Log Po/w (MLOGP) : | 4.12 |
Log Po/w (SILICOS-IT) : | 3.84 |
Consensus Log Po/w : | 3.55 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.16 |
Solubility : | 0.0184 mg/ml ; 0.0000696 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -3.45 |
Solubility : | 0.093 mg/ml ; 0.000352 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.91 |
Solubility : | 0.00323 mg/ml ; 0.0000122 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.62 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | 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 |
---|---|---|
94 %Chromat. | With cobalt(II) chloride; lithium iodide; isoprene In tetrahydrofuran at -78 - 50℃; for 5 h; Inert atmosphere | General procedure: Coupling of Alkyl Halides with t-BuMgCl; Procedure 1 (P1)An alkyl halide (1.0 mmol), decane (63 mg as an internal standard)and LiI (5.3 mg, 0.04 mmol) were added to a dry, nitrogen-flushedtest tube equipped with a rubber septum and a magnetic stir bar.THF (0.8 mL) was added and the solution was cooled to –78 °C usinga dry ice/EtOH bath. t-BuMgCl (2a) (1.5 mL, 0.81 M in THF,1.2 mmol) was added slowly followed by isoprene (136.2 mg, 2.0mmol). To this mixture was added CoCl2 [2.6 mg, 0.02 mmol, as apowder or as a THF solution (0.5 mL, 0.04 M)]. (Note 1: CoCl2should be added after isoprene, otherwise the catalytic performancedecreases significantly). The cold bath was removed and the mixturewas warmed to r.t. (ca. over 10 min), and then heated for 5 h bysuspending the reaction vessel in an oil bath kept at 50 °C. (Note 2:when the reaction mixture was heated at 30 °C during this stage, unidentifiedside reactions occurred resulting in low yields of couplingproducts). The resulting mixture was cooled to 0 °C in an ice bathand the reaction was quenched with aq HCl (5 mL, 1 M). The productwas extracted with Et2O (3 × 20 mL). The combined organiclayer dried over Na2SO4, concentrated and analyzed by gas chromatographyto determine the GC yield. The residue was purified by silicagel column chromatography or by GPC. 1.0 mmol) and n-BuMgCl (2j) (1.0 M in THF, 1.2 mmol) were reactedunder standard conditions.Yield: 94percent (determined by GC using decane as an internal standard). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97 mg | With [((Me)NN2)NiCl]; isopropyl alcohol; sodium iodide; sodium hydroxide In 1,4-dioxane; isopropyl alcohol at 80℃; for 24 h; Inert atmosphere | General procedure: To a solution of NaOH (32 mg, 0.8 mmol, 1.6 equiv), catalyst 1 (8.4mg, 0.025 mmol, 5 molpercent), NaI (37 mg, 0.25 mmol, 0.5 equiv), and i-PrOH (76 μL, 1 mmol, 2 equiv) in dry 1,4-dioxane (2.4 mL), were added alkyl halide (0.5 mmol) and the alkyl-(9-BBN) (1.6 mL, 0.8mmol, 1.6 equiv) under a N2 atmosphere. The mixture was stirred at 80 °C for 24 h. The solution was diluted in Et2O (10 mL), filtered on a short pad of silica, washed with Et2O (3 × 10 mL), and concentrated to dryness under reduced pressure. The residue was purified with a flash purification system to give the coupling product (Tables 1 and 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 0℃; for 1h;Inert atmosphere; Schlenk technique; | A solution of 2-(4-bromophenyl)ethanol (4.43 g, 0.0220 mol) dissolved in CH2Cl2 (50 mL) was cooled to 0C. Next, PPh3 (6.92 g, 0.0264 mol) was added, followed by NBS (4.70 g, 0.0264 mol), and vigorous effervescence in a yellow solution was observed. The mixture was allowed to stir at 0C for 60 minutes. After this time, the yellow solution was treated with saturated sodium bicarbonate solution (20 mL). The deep, dark blue organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The organic layers were combined and then the solvent was removed under reduced pressure to yield a deep, dark blue oil. The oil was purified on a column of silica (~1.5 cm × 20 cm) using EtOAc/hexanes (1:10) as an eluent and collecting the first nearly colourless fraction. Removal of the volatiles under reduced pressure yielded a very pale orange liquid. Yield: 5.38 g (93%). 1H NMR (500 MHz, 22C, CDCl3): 7.43 (d, 2H, 2JHH = 8 Hz, Ar), 7.08 (d, 2H, 2JHH = 8 Hz, Ar), 3.53 (t, 2H, 3JHH = 7 Hz, -CH2CH2-), 3.11 (t, 2H, 3JHH = 7 Hz, -CH2CH2-). |
90% | With bromine; triphenylphosphine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; at 20℃; for 2h; | General procedure: To a stirred solution of triphenylphosphine (1.5 mmol) in dry dichloromethane was added iodine (1.5 mmol)and polymer supported 4-DMAP (0.4 mmol, 40 mol%). Stirring was continued for 2 min; alcohol (1mmol) was then added. The reaction was monitored by TLC. After complete conversion of the alcohol (as indicated byTLC), the reaction was quenched with an aqueous solution of sodium thiosulfate (20 mL). The organic solventswere removed and the aqueous solution extracted with ethylacetate (50 mL). The combined organic layers weredried using sodium sulfate (anhydrous), filtered and concentrated. The residue was purified by column chromatography (2% EtOAc in hexane) to get the desired iodide product. |
90% | With phosphorus tribromide; at 0 - 80℃; for 2.16667h; | The specific operation is as follows: The bromophenylacetic acid was added to 200ml of tetrahydrofuran,Stirring cooled to 0 C after adding lithium aluminum hydride in batches, the end of the addition,After the reaction was heated to 25 ~ 30 C for 2h, 300ml of water and 400ml of dichloromethane were separated,The organic phase was added to 20g of anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure at 30-35 C.Obtained light yellow oil (brominated S1-1): 18.7g, under ice bath,To bromine S1-1 was added dropwise phosphorus tribromide, dropping temperature during the control at 0 ~ 10 ,Dropping is completed, incubated 10min insulation, a white smoke generated, stirring, warming to 75 ~ 80 ,After stirring for 2h, 30ml of saturated sodium bicarbonate solution, 200ml of ethyl acetate,Stirring 20min liquid separation, the organic phase 40 ~ 45 filtrate was concentrated under reduced pressure,A yellow liquid (bromination S2) was obtained: 22.1 g. Yield: 90.0%. |
88.8% | Production Example 4 Synthesis of 4-bromophenethyl bromide 4-Bromophenethyl alcohol (1.3 ml) was treated as in Production Example 1 to give the title compound (2.345 g) as a pale yellow oil (yield: 88.8%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 3.12(2H, t, J=7.4Hz), 3.54(2H, t, J=7.4Hz), 7.09(2H, d, J=8.4Hz), 7.45(2H, d, J=8.4Hz). | |
Part A. Employing method similar to Example 114 Part A but using 4-bromophenethylalcohol (5.0 gm, 24.9 mmol) 4-bromophenethylbromide was prepared as a clear oil. 1 H NMR (CDCl3): 3.15 (t, 2H), 3.58 (t, 2H), 7.10 (d, 2H), 7.45 (d, 2H). | ||
Part A. Employing method similar to Example 114 Part A but using 4-bromophenethylalcohol (5.0 gm, 24.9 mmol) 4-bromophenethylbromide was prepared as a clear oil. 1H NMR (CDCl3): 3.15 (t, 2H), 3.58 (t, 2H), 7.10 (d, 2H), 7.45 (d, 2H). | ||
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h; | To a solution of 2-(4-bromophenyl)ethanol (1.00 g) and tetrabromomethane (3.96 g) in tetrahydrofuran (10 ml) was added triphenylphosphine (2.87 g) at room temperature and the mixture was stirred at the same temperature for 1 hour under nitrogen. The mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-bromo-4-(2-bromoethyl)benzene (2.07 g). NMR (CDCl3, delta): 3.12 (2H, t, J=7.4 Hz), 3.54 (2H, t, J=7.4 Hz), 7.09 (2H, d, J=10.6 Hz), 7.45 (2H, d, J=10.6 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | ||
Multi-step reaction with 2 steps 1.1: ethanol / 2 h / Reflux 2.1: sodium hydroxide / water / 2 h / 120 °C 2.2: 20 °C | ||
With thiourea In ethanol Reflux; | 1.1 p-bromophenethyl mercaptan A solution of p-bromophenethyl bromide (86.87 g, 0.33 mol),Thiourea (30.14 g, 0.396 mol),Anhydrous ethanol (120 ml) was placed in a round bottom flask,Mixed heating reflux,Until there is white precipitation,After filtration,Placed in a single mouth bottle by adding NaOH (135ml, 5M) aqueous solution,Reflow heating for five hours,After dilute hydrochloric acid is acidified,Separating the thiol layer,Dried over anhydrous sodium sulfate,20cm flavor fraction distillation column distillation (distillation range 146-148 ).Bromophenethyl bromide can be obtained by passing 2- (4'-bromophenyl) ethanol to hydrogen bromide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Stage #1: ethyl acetoacetate With potassium <i>tert</i>-butylate; <i>tert</i>-butyl alcohol In tetrahydrofuran at 0℃; for 0.833333h; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In tetrahydrofuran at 0 - 70℃; | |
With sodium ethanolate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With N-ethyl-N,N-diisopropylamine; sodium iodide In dimethyl sulfoxide for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100 % Chromat. | With buta-1,3-diene In tetrahydrofuran at 0℃; for 0.5h; | |
94 %Chromat. | With cobalt(II) chloride; lithium iodide; isoprene In tetrahydrofuran at -78 - 50℃; for 5h; Inert atmosphere; | |
94 %Chromat. | With cobalt(II) chloride; lithium iodide; isoprene In tetrahydrofuran at -78 - 50℃; for 5h; Inert atmosphere; | 1-Bromo-4-hexylbenzene (5rj) General procedure: Coupling of Alkyl Halides with t-BuMgCl; Procedure 1 (P1)An alkyl halide (1.0 mmol), decane (63 mg as an internal standard)and LiI (5.3 mg, 0.04 mmol) were added to a dry, nitrogen-flushedtest tube equipped with a rubber septum and a magnetic stir bar.THF (0.8 mL) was added and the solution was cooled to -78 °C usinga dry ice/EtOH bath. t-BuMgCl (2a) (1.5 mL, 0.81 M in THF,1.2 mmol) was added slowly followed by isoprene (136.2 mg, 2.0mmol). To this mixture was added CoCl2 [2.6 mg, 0.02 mmol, as apowder or as a THF solution (0.5 mL, 0.04 M)]. (Note 1: CoCl2should be added after isoprene, otherwise the catalytic performancedecreases significantly). The cold bath was removed and the mixturewas warmed to r.t. (ca. over 10 min), and then heated for 5 h bysuspending the reaction vessel in an oil bath kept at 50 °C. (Note 2:when the reaction mixture was heated at 30 °C during this stage, unidentifiedside reactions occurred resulting in low yields of couplingproducts). The resulting mixture was cooled to 0 °C in an ice bathand the reaction was quenched with aq HCl (5 mL, 1 M). The productwas extracted with Et2O (3 × 20 mL). The combined organiclayer dried over Na2SO4, concentrated and analyzed by gas chromatographyto determine the GC yield. The residue was purified by silicagel column chromatography or by GPC. 1.0 mmol) and n-BuMgCl (2j) (1.0 M in THF, 1.2 mmol) were reactedunder standard conditions.Yield: 94% (determined by GC using decane as an internal standard). |
98 %Chromat. | With buta-1,3-diene; copper dichloride In tetrahydrofuran at 25℃; for 24h; Schlenk technique; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With trimethylsilyl bromide; 1,1,3,3-Tetramethyldisiloxane; indium tribromide In chloroform at 60℃; for 1h; Sealed tube; Inert atmosphere; | |
Multi-step reaction with 2 steps 1: LiAlH4 / tetrahydrofuran / Heating 2: PBr3 / tetrahydrofuran / Heating | ||
Multi-step reaction with 2 steps 1: LiAlH4 / tetrahydrofuran / 12 h / Heating 2: HBr, H2SO4 |
Multi-step reaction with 2 steps 1: LiAlH4 2: aq. HBr, H2SO4 | ||
With indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane; trimethylsilyl cyanide In chloroform at 60℃; Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 - 30 °C 2: phosphorus tribromide / 2.17 h / 0 - 80 °C | ||
Multi-step reaction with 3 steps 1: indium(III) bromide; 1,1,3,3-Tetramethyldisiloxane / chloroform / 2.08 h / 0 - 60 °C / Schlenk technique; Inert atmosphere 2: triethylamine / dichloromethane / 0.75 h / 0 °C / Schlenk technique; Inert atmosphere 3: lithium bromide / acetone / 0 - 50 °C / Schlenk technique; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 76 percent / K2CO3 / dimethylformamide / 10 h / 50 °C 2: Cs2CO3 / (S)-1,1'-binaphthyl derivative / toluene / 6 h / -40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 76 percent / K2CO3 / dimethylformamide / 10 h / 50 °C 2: Cs2CO3 / (S)-1,1'-binaphthyl derivative / toluene / 6 h / -40 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 18h; | 11.a To a solution of 2- (4-BROMOPHENYL) ethanol (1.2 g, 6.0 mmol) in CH2CL2 (50 mL) at RT under nitrogen was added CBr4 (1.98 g, 5.8 mmol) and PPH3 (1.57 g, 5.8 mmol). After stirring at RT for 18 h the reaction mixture was concentrated and the residue diluted with ET20 (30 mL) resulting in precipitation of triphenylphosphine oxide. The ethereal solution was decanted, evaporated and purified by flash chromatography (silica, hexane) to provide the title compound as a clear oil (59%). 1H NMR (DMSO-d6) 8 7.45 (d, 2 H), 7.15 (d, 2 H), 3.51 (t, 2 H), 3.17 (t, 2 H); 13C NMR (DMSO-d6) 8 138.1, 133.4, 131.2, 122.5, 38.5, 27.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃; for 6h; Inert atmosphere; | ||
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 80℃; for 6h; | 33 To a solution of (αS,βR)-4-hydroxynorephedrine (500 mg) and 4-bromophenylethyl bromide (500 mg) in N,N-dimethylformamide (5 ml) was added N,N-diisopropylethylamine (0.5 ml), and the mixture was stirred for 6 hours at 80° C. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residual oil was diluted in tetrahydrofuran (10 ml). To the solution was added di-tert-butyl dicarbonate (1 g) at room temperature, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was evaporated under pressure and the residue was purified by column chromatography on silica gel to give 4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl](tert-butyloxycarbonyl)amino]ethyl]phenyl bromide (520 mg). MS (m/z): 550 (M+H) | |
With diisopropylamine In N,N-dimethyl-formamide at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.6% | With potassium carbonate | Synthesis of 1-[1-(4-bromophenethyl)piperidin-4-yl]-6-acetamidomethylindole Synthesis of 1-[1-(4-bromophenethyl)piperidin-4-yl]-6-acetamidomethylindole Potassium carbonate (1.0 g) was added to a solution of 1-(piperidin-4-yl)-6-acetamidomethylindole (0.20 g) obtained in Example 386-1) and 4-bromophenethyl bromide (0.16 g) obtained in Production Example 4 in N,N-dimethylformamide (15 ml) and the resultant mixture was stirred at 70° C. for 6 hr. Then the reaction mixtured were concentrated under reduced pressure and the residue was partitioned between chloroform (40 ml) and water (15 ml). The chloroform layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol system) and then crystallized from ethyl acetate/hexane to give the title compound (0.25 g) as a pale yellow powder (yield: 74.6%). m.p.: 140-141° C. 1H-NMR(400 MHz,DMSO-d6); δ(ppm)) 1.86(3H, s), 1.88-2.03(4H, m), 2.19-2.28(2H, m), 2.56-2.62(2H, m), 2.73-2.79(2H, m), 3.05-3.12(2H, m), 4.26-4.35(1H, m), 4.34(2H, d, J=6.0Hz), 6.41(1H, d, J=3.2Hz), 6.97(1H, d, J=8.0Hz), 7.25(2H, d, J=8.0Hz), 7.32(2H, d, J=8.0Hz), 4.64-6.93(1H, dd, J=8.0,1.2Hz), 7.23(2H, d, J=8.0Hz), 7.40(1H,br-s), 7.45-7.50(4H, m), 8.25-8.31(1H, m). ESI-Mass; 455 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; potassium carbonate In <i>N</i>-methyl-acetamide; water; toluene | 9 cis-2-(4-Bromophenethyl)-3a,4,7,7a-tetrahydroisoindoline STR46 EXAMPLE 9 cis-2-(4-Bromophenethyl)-3a,4,7,7a-tetrahydroisoindoline STR46 A mixture of 0.6 g of cis-3a,4,7,7a-tetrahydroisoindoline, 1.4 g of 4-bromophenethyl bromide, 1.0 g of potassium carbonate and 3 mL of dimethylformamide was stirred and heated in a 90° oil bath for 1 hour. Toluene (20 mL) and water (20 mL) were added and the aqueous layer was extracted with toluene. Addition of 10 mL of 10% hydrochloric acid to the toluene solution resulted in the formation of three layers. The two lower layers were made basic with aqueous sodium hydroxide solution. Extraction with methylene chloride gave 0.89 g of crude product which on short-path distillation gave 0.63 g of cis-2-(4-bromophenethyl)-3a,4,7,7a-tetrahydroisoindoline. 'H NMR (in CDCl3) δ7.4 (d, 2H); 7.0 (d, 2H); 5.8 (m, 2H); 3.0 (m, 2H); 2.6-2.8 (m, 4H); 2.4 (m, 2H); 2.1-2.3 (m, 4H) and 1.9 (d, 2H). The fumarate had m.p. 166°-167° after crystallization from ethanol. Anal. Calcd. for C20 H24 BrNO4: C, 56.88; H, 5.73; N, 3.32; Found: C, 56.91; H, 5.64; N, 3.21 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium carbonate In acetonitrile at 150℃; for 0.333333h; microwave irradiation; | A6.m m) Preparation of intermediate compound 24; A mixture of intermediate compound 3-phenethylamino-lH-pyrazin-2-one (0.4 g, 0.0019 mol) (prepared according to the method described for intermediate compound 2), 4-bromophenethyl bromide (0.443 ml, 0.0029 mol), K2CO3 (0.401 g, 0.0029 mol) in AcCN (4 ml) was heated in microwave at 150 0C for 20 min. The solids were filtered off and washed with CH2Cl2. The filtrate was evaporated. The residue was purified by column chromatography. The desired fraction were collected and evaporated.. The product was precipitated with DIPE affording 0.365 g of intermediate compound 24 (48 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium iodide In N,N-dimethyl-formamide at 50℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium sulfite In water at 105 - 107℃; for 18h; | 210.c Sodium sulfite (4.75 g, 37.68 mmol) was added to a suspension of 1-bromo-4-(2-bromo-ethyl)-benzene (5.00 g, 18.94 mmol) in water (60 mL). The reaction mixture was heated at 105-107° C. for 18 hours and then cooled to -5° C. The formed precipitate was removed by filtration, washed with water (50 mL) and dried under vacuum to give 4.33 g (86% yield) of the title compound.1H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (d, 2H), 7.18 (d, 2H), 2.88-2.80 (m, 2H), 2.68-2.61 (m, 2H); MS (ESI) m/z 263 [M-1]-(corresponding sulfonic acid, MW=265). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 61% 2: 2% 3: 5% | With FeCl2(dppbz)2; zinc(II) chloride In tetrahydrofuran at 0 - 60℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With (trimethylsilyl)methylzinc iodide; iron(III) chloride; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran at 0 - 30℃; for 49h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With copper(l) iodide; C16H22ClN3Ni; caesium carbonate; sodium iodide In 1,4-dioxane at 100℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: uracil With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In N,N-dimethyl-formamide | 1-(4-Bromo-benzyl)-1H-pyrimidine-2,4-dione (35) A suspension of uracil (4.94 g, 44.0 mmol) and potassium carbonate (4.7 g, 33.9 mmol) in anhydrous DMF (60 ml) was stirred at room temperature for 1 h, then 4-bromobenzylmethyl bromide (8.47 g, 33.9 mmol) was added. After stirring overnight, the mixture was purified to give compound 35 (3.15 g, 33% yield). 1H NMR (DMSO-d6) δ: 4.85 (s, 2H, PhCH2), 5.60 (d, 1H, H5, J = 7.8 Hz), 7.26 (d, 2H, H arom., J = 8.4 Hz), 7.60 (dt, 2H, H arom., J = 8.4 Hz, J = 2 Hz), 7.76 (d, 1H, H6, J = 7.8 Hz), 11.34 (bs, 1H, NH). 13C NMR (DMSO-d6) δ: 50.60 (PhCH2), 102.32 (C5), 121.69 (C arom.), 130.58 CH arom.), 132.39 (CH arom.), 137.17 (CH arom.), 146.38 (C6), 151.84 (C2), 164.48 (C4). MS (ESI-TOF) m/z 281.0 and 283.0 (M+H)+, 303.0 and 305.0 (M+Na)+, 325.0 and 327.0 (M+2Na)+, 335.0 and 337.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N,N,N,N,-tetramethylethylenediamine; [((Me)NN2)NiCl] In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: tert-butylmagnesium chloride With bis(acetylacetonate)nickel(II); 1-(2-carboxyethyl)-3-mesityl-1H-imidazol-3-ium chloride; lithium tert-butoxide In tetrahydrofuran; diethyl ether at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In tetrahydrofuran; diethyl ether at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 1-bromo-4-(2-bromoethyl)benzene With 1,2-bis(bis(3,5-di-tert-butylphenyl)phosphino)benzene; dichloro{1,2-[bis(3,5-di-tert-butylpheny)phosphino-κP]benzene}iron(II) In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 4-methoxyphenyl magnesium bromide In tetrahydrofuran at 40℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-bromo-4-(2-bromoethyl)benzene With magnesium In tetrahydrofuran for 1h; Reflux; Inert atmosphere; Stage #2: oxalic acid diethyl ester In tetrahydrofuran at -10℃; for 1.5h; Inert atmosphere; Stage #3: With hydrogenchloride In tetrahydrofuran; water Inert atmosphere; | General procedure for the preparation of 2-oxo-4-arylbutanoic acids 1: General procedure: Magnesium turnings (13.2 g, 0.55 mol) were placed in dry THF (25 mL) undernitrogen. A small amount (10 mL) of (2-bromoethyl)benzene (92.5 g, 0.50 mol) dissolvedin dry THF (300 mL), added to the magnesium slurry and stirred for a few minutes withwarming until the reaction commenced. The remainder of the (2-bromoethyl)benzenesolution was added dropwise to maintain reflux over an hour, then the reaction mixturewas aged at reflux for an additional an hour. The reaction mixture was cooled to 25 °C. In a separate flask, diethyl oxalate (88.2 g, 0.6 mol) was dissolved in dry THF (100mL) and cooled to -10 °C. The supernatant solution of (2-phenylethyl)magnesiumbromide was sucked under nitrogen through a sintered-glass filter into a dropping funnel.The reaction temperature was held at -10 °C as the solution of Grignard reagent wasadded dropwise over an hour to the diethyl oxalate. The sintered-glass funnel anddropping funnel were then rinsed with dry THF (100 mL), and the rinse was added to thebatch. The reaction mixture was allowed to stand for 30 min and then quenched byaddition of 3 M HCl (145 mL).Hexane (500 mL) was added, and the aqueous layer was discarded. The organicphase was washed with brine (100 mL) and saturated NaHCO3 (100 mL), until theaqueous layer measured to pH 5.0. The organic phase was dried with anhydrous Na2SO4.Filtered and washed with hexane, and the combined layers were concentrated to an oil invacuum. The crude keto ester (103.0 g) was vacuum distilled at 105-110 °C (0.2-0.3 mmHg) to afford a colourless oil 90.0 g with 60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: tris-iso-propylsilyl acetylene With ethylmagnesium bromide In tetrahydrofuran at 35℃; Inert atmosphere; Stage #2: 1-bromo-4-(2-bromoethyl)benzene With dichloro{1,2-[bis(3,5-di-tert-butylpheny)phosphino-κP]benzene}iron(II) In tetrahydrofuran at 70℃; for 2h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate In acetone for 48h; Reflux; | 4.4. Synthesis of benzyl phenyl ether analogs (6a-d) General procedure: While benzyl phenyl ether (6a) is commercially available (Sigma-Aldrich), analogs 6b-d were synthesized as follows: Phenol (0.01 mmol) and an appropriate alkyl bromide (0.01 mmol; cinnamyl bromide, 4-bromobenzyl bromide and 4-bromophenethyl bromide for the synthesis of 6b, 6c an 6d, respectively) were dissolved in 40 mL dry acetone and K2CO3 (0.01 mmol) was added. The reaction mixture was heated under reflux for 48 h, filtered while hot and the residual K2CO3 was washed with acetone (10 mL). The filtrate was cooled to room temperature and concentrated under reduced pressure. The resulting residue was recrystallized twice from ethanol to yield the target ethers [40]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate In N,N-dimethyl-formamide | |
62.6% | With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 18h; Inert atmosphere; | Ethyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl) butanoate (I-03) Intermediate I-02 (4.1 g, 22.58 mmol) was dissolved in anhydrous DMF (20 mL). Sodium methanesulphinate (0.7 g, 5.80 mmol) and Cs2CO3 (14.7 g, 45.16 mmol) were added to the solution under argon. The mixture was stirred at 50 for 18 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl ether and water. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel with petroleum/ethyl acetate (10/1~5/1) to give 5.1 g (62.6%) of I-03 as a colorless liquid. 1H NMR (400 MHz, Chloroform-d) δ 7.48-7.38 (d, J = 8.3 Hz, 2H), 7.15-7.00 (d, J = 8.3 Hz, 2H), 4.35-4.22 (qd, J = 7.1, 1.2 Hz, 2H), 3.08-2.97 (s,3H), 2.78-2.65 (m, 1H), 2.55-2.42 (ddd, J = 23.4, 11.6, 4.8 Hz, 2H), 2.28-2.08 (m, 1H), 1.73-1.65 (s, 3H), 1.42-1.30 (t, J = 7.1 Hz, 3H). MS (EI) m/z: (M+, 362). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate In acetone for 24h; Reflux; | 4.2. Synthesis of the C6-substituted chromone derivatives (3a-o) General procedure: To a solution of 6-hydroxy-4-chromone (3 mmol) in 20 mL of acetone, were added anhydrous potassium carbonate (6 mmol) and the appropriate alkyl bromide (6 mmol). The mixture was stirred and heated at reflux for 24 h. The mixture was filtered through a pad of celite and the solvent was removed in vacuo to yield a reddish residue. This crude product was triturated with 50 mL diethyl ether, filtered and dried overnight at 60 °C. For 3b and 3o, the residue obtained after removal of the reaction solvent was purified via neutral alumina column chromatography using CH2Cl2-ethylacetate (4:1) as an eluent. The target chromones were purified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; sodium iodide In acetonitrile at 60℃; | tert-Butyl (S)-1-((S)-1-((S)-1-(4-bromophenethyl)piperidin-3-ylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (Intermediate 63): General procedure: A mixture of tert-butyl (S)-1-((S)-3,3-dimethyl-1-oxo-1-((S)-piperidin-3-ylamino)butan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (Intermediate 49; 100 mg, 0.25 mmol), 1-bromo-4-(2-bromoethyl)benzene (66 mg, 0.25 mmol), sodium bicarbonate (63 mg, 0.75 mmol) and sodium iodide (9.4 mg, 0.06 mmol) in acetonitrile (3.0 mL) was heated at 60 °C overnight. The mixture was allowed to cool and was concentrated under reduced pressure. The residue was partitioned between EtOAc and water, and the organic layer was concentrated. The crude material was purified by reverse phase HPLC (gradient of 40-70% MeCN in H2O containing 0.2% NH4OH) to give the product as a sticky gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With potassium carbonate In acetone for 24h; Reflux; | 15 Synthesis of the C7 substituted chromone derivatives (3a-o) General procedure: 7-Hydroxy-4-chromone (3 mmol) was dissolved in 20 ml of acetone. To this solution, anhydrous potassium carbonate (6 mmol) and the appropriate alkyl bromide (6 mmol) were added, and the reaction mixture was heated at reflux and stirred for 24 h. The reaction was filtered through a pad of Celite and the solvent was subsequently removed in vacuo. The crude residue was triturated with 50 mL diethyl ether, the resulting solid material was collected by filtration and dried overnight at 60 C. Compounds 3b and 3o required column chromatographic purification. For these compounds, the residue obtained after removal of the reaction solvent was chromatographed using neutral alumina as stationary phase and dichloromethane-ethylacetate (4:1) as an eluent. The chromone derivatives were recrystallized from ethanol. 4.2.15 7-[2-(4-Bromophenyl)ethoxy]-4H-chromen-4-one (3o) The title compound (white powder) was prepared by reacting 7-hydroxychromone and 4-bromophenethyl bromide in acetone, with a yield of 25%: mp 93.1-93.8 °C (ethanol). 1H NMR (Bruker Avance III, 600 MHz, CDCl3) δ 8.07 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.92 (dd, J = 8.9, 2.4 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.24 (d, J = 6.0 Hz, 1H), 4.20 (t, J = 6.7 Hz, 2H), 3.07 (t, J = 6.7 Hz, 2H). 13C NMR (Bruker Avance III, 150 MHz, CDCl3) δ 176.92, 163.04, 158.11, 154.80, 136.63, 131.63, 130.67, 127.22, 120.60, 118.84, 114.66, 112.92, 100.94, 68.77, 34.85. HRMS m/z: calcd for C17H13BrO3, 344.0048, found 344.0033. Purity (HPLC): 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
620 mg | A mixture of C10H11NO2 (300 mg, 1.69 mmol), C8H8Br2 (1.00 g, 3.79 mmol), and 2-propanol (10 mL) was heated to reflux for 23 h. The resulting solution was cooled to room temperature, and evaporated. The crude was dissolved in MeOH (15 mL), cooled to 0 C. in ice-bath, and then NaBH4 (420 mg, 11.1 mmol) was added in portions under N2. The mixture was stirred for another 20 min and then concentrated. The residue was treated with CHCl3 (30 mL) and H2O (30 mL) and then the organic layer was dried over MgSO4, filtered and evaporated. The purification is performed by the precipitation method. The crude product is dissolved with 5 mL of EtOAc, and then the product is precipitates with 10 mL of n-hexane to afford a beige solid (620 mg, 1.71 mmol). | |
620 mg | A mixture of C10H11NO2 (300 mg, 1.69 mmol), CsHsBn (1.00 g, 3.79 mmol), and 2-propanol ( 10 mL) was heated to reflux for 23 h. The resulting solution was cooled to room temperature, and evaporated. The crude was dissolved in MeOH (15 mL), cooled to 0C in ice-bath, and then NaBH4 (420 mg, 11.1 mmol) was added in portions under N2. The mixture was stirred for another 20 min and then concentrated. The residue was treated with CHCb (30 mL) and H2O (30 mL) and then the organic layer was dried over MgS04, filtered and evaporated. The purification was performed by the precipitation method. The crude product was dissolved with 5 mL of EtOAc, and then the product was precipitates with 10 mL of /7-hexane to afford a beige solid (620 mg, 1.71 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71 %Chromat. | With cobalt(II) chloride; lithium iodide; isoprene In tetrahydrofuran at -78 - 50℃; for 5h; Inert atmosphere; | |
71 %Chromat. | With cobalt(II) chloride; lithium iodide; isoprene In tetrahydrofuran at -78 - 50℃; for 5h; Inert atmosphere; | 1-Bromo-4-(3-methylpentyl)benzene (5rg) General procedure: Coupling of Alkyl Halides with t-BuMgCl; Procedure 1 (P1)An alkyl halide (1.0 mmol), decane (63 mg as an internal standard)and LiI (5.3 mg, 0.04 mmol) were added to a dry, nitrogen-flushedtest tube equipped with a rubber septum and a magnetic stir bar.THF (0.8 mL) was added and the solution was cooled to -78 °C usinga dry ice/EtOH bath. t-BuMgCl (2a) (1.5 mL, 0.81 M in THF,1.2 mmol) was added slowly followed by isoprene (136.2 mg, 2.0mmol). To this mixture was added CoCl2 [2.6 mg, 0.02 mmol, as apowder or as a THF solution (0.5 mL, 0.04 M)]. (Note 1: CoCl2should be added after isoprene, otherwise the catalytic performancedecreases significantly). The cold bath was removed and the mixturewas warmed to r.t. (ca. over 10 min), and then heated for 5 h bysuspending the reaction vessel in an oil bath kept at 50 °C. (Note 2:when the reaction mixture was heated at 30 °C during this stage, unidentifiedside reactions occurred resulting in low yields of couplingproducts). The resulting mixture was cooled to 0 °C in an ice bathand the reaction was quenched with aq HCl (5 mL, 1 M). The productwas extracted with Et2O (3 × 20 mL). The combined organiclayer dried over Na2SO4, concentrated and analyzed by gas chromatographyto determine the GC yield. The residue was purified by silicagel column chromatography or by GPC. According to P1, 1-bromo-4-(2-bromoethyl)benzene (4r) (230 mg,1.0 mmol) and s-BuMgCl (2g) (0.76 M in THF, 1.2 mmol) were reactedunder standard conditions.Yield: 71% (determined by GC using decane as an internal standard). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium azide In N,N-dimethyl-formamide at 80℃; for 16h; | 3 The synthesis of l-(2-azidoethyl)-4-bromobenzene (0147-2). To a solution of compound 0147-1 (5 g, 18.9 mmol) in DMF (20 mL) was added NaN3(2.46 g, 37.9 mmol). The mixture was stirred at 80 °C for 16 h. Then added water, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the desired product 0147-2 (4 g, yield: 94%) as a yellow solid. |
With sodium azide In dimethyl sulfoxide at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 4-methoxyphenylacetylen With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Stage #2: 1-bromo-4-(2-bromoethyl)benzene With sodium iodide In tetrahydrofuran; hexane for 48h; Inert atmosphere; Reflux; | |
Stage #1: 4-methoxyphenylacetylen With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; Stage #2: 1-bromo-4-(2-bromoethyl)benzene With sodium iodide In tetrahydrofuran; hexane at 20℃; Reflux; | ||
Stage #1: 1-bromo-4-(2-bromoethyl)benzene; 4-methoxyphenylacetylen With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Stage #2: With sodium iodide In tetrahydrofuran Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine In acetonitrile at 20℃; for 15h; | |
50% | With potassium carbonate In acetonitrile at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium carbonate In acetonitrile at 20℃; for 16h; | |
48% | With triethylamine In acetonitrile at 20℃; for 24h; | |
With potassium carbonate In acetonitrile at 20℃; | 300.1 Step 1: The reaction mixture of 1-bromo-4-(2-bromoethyl)benzene (300 mg, 1.13 mmol), potassium carbonate (471.24 mg, 3.41 mmol) and pyrrolidine (0.09 ml, 1.14 mmol) in acetonitrile (6 mL)was stirred at rt overnight. The reaction mixture was then filtered. The filtrate was concentrated down and the residue was purified by silica gel column chromatography to afford 1-(4- bromophenethyl)pyrrolidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97 mg | With [((Me)NN2)NiCl]; isopropyl alcohol; sodium iodide; sodium hydroxide; In 1,4-dioxane; isopropyl alcohol; at 80℃; for 24h;Inert atmosphere; | General procedure: To a solution of NaOH (32 mg, 0.8 mmol, 1.6 equiv), catalyst 1 (8.4mg, 0.025 mmol, 5 mol%), NaI (37 mg, 0.25 mmol, 0.5 equiv), and i-PrOH (76 muL, 1 mmol, 2 equiv) in dry 1,4-dioxane (2.4 mL), were added alkyl halide (0.5 mmol) and the alkyl-(9-BBN) (1.6 mL, 0.8mmol, 1.6 equiv) under a N2 atmosphere. The mixture was stirred at 80 C for 24 h. The solution was diluted in Et2O (10 mL), filtered on a short pad of silica, washed with Et2O (3 × 10 mL), and concentrated to dryness under reduced pressure. The residue was purified with a flash purification system to give the coupling product (Tables 1 and 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74 mg | With tert-Amyl alcohol; [((Me)NN2)NiCl]; sodium iodide; sodium hydroxide In 1,4-dioxane at 80℃; for 24h; Inert atmosphere; | Aryl-Alkyl Coupling Reactions; General Procedure with Ph-(9-BBN) General procedure: To a solution of NaOH (32 mg, 0.8 mmol, 1.6 equiv), catalyst 1 (8.4mg, 0.025 mmol, 5 mol%), NaI (37 mg, 0.25 mmol, 0.5 equiv), and i-PrOH (76 μL, 1 mmol, 2 equiv) in dry 1,4-dioxane (4 mL), were added alkyl halide (0.5 mmol) and phenyl-(9-BBN) (1.6 mL, 0.8 mmol, 1.6 equiv) under a N2 atmosphere. The mixture was stirred at 80 °C for 24 h. The solution was diluted in Et2O (10 mL), filtered on a short pad of silica, washed with Et2O (3 × 10 mL), and concentrated to dryness under reduced pressure. The residue was purified with a flash purification system to give the coupling product (Tables 5 and 6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.8% | Stage #1: 2-acetylaminomalonic acid diethyl ester With sodium ethanolate at 0 - 20℃; for 2h; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In ethanol at 80℃; for 20h; | Preparation of diethyl 2-acetamido-2-(4-bromophenethyl)malonate (6) Sodium (3.66 g, 159.1 mmol) was added to absolute EtOH(250 mL). After sodium dissolved completely, diethyl acetamidomalonate(36.2 g, 166.7 mmol) was added in portions at 0 C.The solution was then allowed to return to room temperature andstirred for further 2 h. Then a solution of 1-bromo-4-(2-bromoethyl)benzene (5, 40 g, 151.5 mmol) in absolute EtOH(40 mL) was added. The mixture was heated at 80 C for 20 h, then filtered and concentrated. The residue was diluted with EtOAc(300 mL), washed with brine, dried over Na2SO4, filtered andconcentrated. The residue was purified by silica gel flash columnchromatography (EtOAc/PE 1:3) to afford compound 6 (20 g,32.8% yield) as yellow solid. Mp: 35e38 C; 1H NMR (300 MHz,CDCl3) d 7.38 (d, J 8.4 Hz, 2H), 7.02 (d, J 8.1 Hz, 2H), 6.76 (s, 1H),4.25e4.16 (m, 4H), 2.69e2.63 (m, 2H), 2.46e2.41 (m, 2H), 1.99 (s,3H), 1.25 (t, J 6.9 Hz, 6H); MS (ESI) m/z 400.1 (MH). |
32.8% | Stage #1: 2-acetylaminomalonic acid diethyl ester With sodium In ethanol at 20℃; for 2h; Cooling with ice; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In ethanol at 80℃; for 18h; Cooling with ice; | 2.1 (1) Preparation of diethyl 2-acetylamino-2-(4-bromophenylethyl)malonate Sodium metal (3.66g, 159.1mmol) was dissolved in 250mL of absolute ethanol, Diethyl acetamidomalonate (36.2 g, 166.7 mmol) was added portionwise under ice-cooling and stirred at room temperature for 2 hr. A solution of 1-bromo-4-(2-bromoethyl)benzene (40 g, 151.5 mmol) in absolute ethanol was added dropwise under ice-cooling, and refluxed at 80 ° C for 18 hours. filtered, and the filtrate was concentrated, and the residue was dissolved in 300 ml of ethyl acetate. wash once with saturated ammonium chloride solution, wash twice with water, and wash once with saturated sodium chloride solution. Dry over anhydrous sodium sulfate. concentrated and separated by column chromatography. The eluent was petroleum ether: ethyl acetate = 3:1. gave 20 g of a yellow solid, yield 32.8%. Melting point 35-38 ° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With triethylamine In acetonitrile at 70℃; for 4h; | |
64% | With triethylamine In acetonitrile at 85℃; for 18h; | II (1-(4-bromophenethyl)piperidin-4-yl)diphenylmethanol (1-(4-bromophenethyl)piperidin-4-yl)diphenylmethanol To a vial was added the diphenyl(piperidin-4-yl)methanol (0.496 g, 1.855 mmol), 1-bromo-4-(2-bromoethyl)benzene (0.258 ml, 1.69 mmol) and acetonitrile (10 mL). The TEA (0.353 mL, 2.53 mmol) was then added and the reaction stirred at 85° C. for 18 h then cooled to rt. The reaction was diluted with water and extracted with EtOAc (3*15 mL). The EtOAc layer was collected and dried with MgSO4, filtered and adsorbed to silica then purified by MPLC (15 min, 0-10% MeOH:DCM). to produce pure (1-(4-bromophenethyl)piperidin-4-yl)diphenylmethanol (0.488 g, 1.083 mmol, 64% yield). 1H NMR (400 MHz, CDCl3): δ 7.50-7.46 (m, 4H), 7.38 (d, J=8.3 Hz, 2H), 7.34-7.27 (m, 4H), 7.18 (tt, J=7.3 Hz, 1.8 Hz, 2H), 7.06 (d, J=8.4 Hz, 2H), 3.06-3.00 (m, 2H), 2.77-2.72 (m, 2H), 2.58-2.52 (m, 2H), 2.50-2.41 (m, 1H), 2.15-2.00 (m, 3H), 1.56-1.49 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 145.8, 139.3, 131.4, 130.4, 128.2, 126.6, 125.8, 119.8, 79.5, 60.4, 54.0, 44.1, 33.1, 26.4, 21.1 LCMS Retention time: 3.969 min. LCMS purity 99.8%. HRMS (ESI): m/z calcd for C26H28BrNO [M+H]+ 450.1354. found 450.1427. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.6% | 5.3.2 Synthesis of compound 5.3.2 Step 1. Synthesis of ethyl 4-(4-bromophenethyl)tetrahydro-2H-pyran-4- carboxylate [5.3.2a] 5.3.2a A solution of LDA (2.465 ml, 4.93 mmol) and THF (5.0 mL) was cooled at -78 oC. Ethyl tetrahydro-2H-pyran-4-carboxylate (600 mg, 3.79 mmol) in THF (2.0 mL) was added dropwise to above solution and the solution was stirred at -78 C for 30 minutes. Then 1- bromo-4-(2-bromoethyl)benzene (0.873 ml, 5.69 mmol) was added. The mixture was stirred at -78 oC for 30 minutes and warmed to room temperature. The reaction was quenched with saturated aqueous NH4CI solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated on to silica. Purification by silica gel column chromatography (EtO Ac/heptane, 0 to 70%) to afford 5.3.2a (85.4 mg, 6.6% yield). LCMS (m/z) 343.1 [M+H]+. 1H NMR (400 MHz, CDCI3) delta ppm 1.31 (t, J=7.24 Hz, 3 H) 1.50 - 1.62 (m, 2 H) 1.72 - 1.91 (m, 2 H) 2.15 (d, J=12.13 Hz, 2 H) 2.38 - 2.60 (m, 2H) 3.48 (td, J=1 1.74, 1.96 Hz, 2 H) 3.86 (dt, J=1 1.84, 3.47 Hz, 2 H) 4.21 (q, J=7.17 Hz, 2 H) 7.02 (d, J=8.22 Hz, 2 H) 7.40 (d, J=8.22 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.7% | Stage #1: benzoimidazole With potassium hydroxide In dimethyl sulfoxide at 20℃; for 2h; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In dimethyl sulfoxide at 20℃; for 24h; | Method Al: N- alkylation of Benzimidazole (VNPP319C and VNPP346). General procedure: DMSO (10 mL, dried over molecular sieves) was added to KOH (0.95 g, 16.96 mmol, crushed pallets) and the mixture was stirred for 5 min. Benzimidazole (0.5 g, 4.23 mmol) was then added and stirred at room temperature for 2 h prior to the addition of corresponding 4- bomophenylakyl bromide (8.46 mmol). Reaction mixture stirred for 24 h, poured on to ice- water mixture, filtered, dried and purified by FCC l-(4-bromophenethyl)-lH-benzo[d]imidazole (VNPP319C) Hz, 2 H, CH2), 4.38 (t, J = 6.87 Hz, 2 H, =N-CH2), 6.86 (d, J = 8.09 Hz, 2 H, Ar-22 and 62 Hs), 7.27-7.34 (m, 2 H, Ar-51 and 61 Hs), 7.35-7.41 (comp, 3 H, Ar-71, 32 and 52 Hs ), 7.58 (s, 1 H, Ar- 21 H), 7.77-7.85 (dd, J = 6.65, 1.75 Hz, 1 H, Ar-41 H); 13C NMR (101 MHz, CDC13) δ 35.6, 46.4, 109.4, 120.6, 121.0, 122.2, 123.0, 130.3 (2 X C), 131.9 (2 X C), 133.4, 136.4, 142.9, 143.9 14 033063 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: diphenylphosphane With potassium <i>tert</i>-butylate In tetrahydrofuran Inert atmosphere; Schlenk technique; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Schlenk technique; | Synthesis of Ph2PCH2CH2(4-BrC6H4) General procedure: A solution of KPPh2 was first prepared by adding HPPh2 (700 μL, 4.00 mmol) via syringe to a suspension of KOtBu (0.898 g, 8.00 mmol) in THF (40 mL). The intensely orange solution was cooled to 0°C, and then a solution of 4-bromobenzyl bromide in THF (20 mL) was added via cannula turning the solution nearly colourless. The mixture was left in the cooling bath and allowed to warm slowly to room temperature overnight. The next day, the volatiles were removed under reduced pressure and then the remaining white solid was redissolved in CH2Cl2 (40 mL). Degassed water (20 mL) was added via syringe, and then the mixture was rapidly stirred for several minutes. The organic layer was separated, and the aqueous layer was extracted with an additional volume of CH2Cl2 (20 mL). The organic layers were combined and dried over anhydrous Na2SO4. Upon filtering and removing the solvent from the filtrate under reduced pressure, a colourless solid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.149 g | With dichloro{1,2-[bis(3,5-di-tert-butylpheny)phosphino-κP]benzene}iron(II) In tetrahydrofuran; hexane at 0 - 60℃; for 18h; Schlenk technique; chemoselective reaction; | A typical procedure for the reactions in Table 2: Synthesis of (cycloheptylethynyl)triisopropylsilane (3a) General procedure: Following to the general procedure of lithium alkynylborates, lithium (triisopropylsilyl)ethynyl trimethylborate 2 in THF/hexane was prepared in a well-dried Schlenk tube from triisopropylsilylacetylene (0.137 g, 0.75 mmol), BuLi in hexane (0.479 mL, 1.57 M, 0.75 mmol), and B(OMe)3 (80.5 mg, 86.6 L, 0.78 mmol). To a resulting reaction mixture were added to chlorocycloheptane (66.0 mg, 0.50 mmol), and FeCl2(SciOPP) (0.25 mL, 0.10 M in THF, 25 μmol, 5 mol %) at 0 °C. The reaction was carried out at 80 °C for 5 h. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl (2.0 mL). The aqueous layer was extracted with ethyl acetate five times, passed through a pad of Florisil, and then concentrated in vacuo. After flash chromatography with hexane, the title compound (0.106 g, 76% yield, 99% pure on GC analysis) was obtained as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With copper(I) oxide; lithium methanolate; pyrographite In ethanol at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 78% 2: < 10 %Chromat. | With copper(l) iodide; lithium tert-butoxide In N,N-dimethyl-formamide at 60℃; for 24h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: Isobutyronitrile With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 0.5h; Schlenk technique; Inert atmosphere; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In tetrahydrofuran at -78 - 20℃; Schlenk technique; Inert atmosphere; | |
Stage #1: Isobutyronitrile With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5h; Schlenk technique; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In tetrahydrofuran at 20℃; for 12h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In N,N-dimethyl-formamide at 60℃; for 16h; | 4.A 1-[2-(4-bromophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine A solution of 1-[2-(4-nitrophenyl)ethyl]piperazine (300mg, 1.3 mmol), 1-bromo-4-(2-bromoethyl)benzene (400mg, 1.5 mmol), and triethylamine (0.89 mL, 6.4 mmol) in DMF (5 mL) was heated to 60 °C for 16 hours. LC showed formation of the desired product. The desired product was purified by silica gel chromatography (10% MeOH in EtOAc). LC-MS (IE, m/z): 420 (M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.88 g | With N-ethyl-N,N-diisopropylamine at 50℃; for 16h; | 6.A 1,4-Bis[2-(4-bromophenyl)ethyl]piperazine Hunig's Base (3.0 ml, 17 mmol) was added to a stirred solution of piperazine (250 mg, 2.9 mmol) and 1-bromo-4-(2-bromoethyl) benzene (0.89 ml, 5.8 mmol) at 50 °C for 16 hours. The reaction was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated and dried over Na2SO4 and evaporated to dryness. The residue was purified thru 40 gram ISCO Redi-sep column and eluted with 0-5% MeOH in DCM to give yellow solids of 1,4-bis[2-(4-bromophenyl)ethyl]piperazine (0.88 g, 1.95 mmol). LC-MS (IE, m/z): 453 [M + 1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogen bromide; acetic acid In hexane at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In toluene at 105℃; Sealed tube; | 9.1 Step 5. l-[3-(2,4-Dichloro^henoxy)^ropyl]-3-(3-diethylamino-propyl)-2-imino-5-phenyl- 2,3-dihydro-lH-benzoimidazole General procedure: A solution of the freebase of l-(3-diethylamino-propyl)-6-phenyl benzoimidazol-2-ylamine (28 mg, 0.087 mmol, Example 11, Step 4) and 2-(3- bromopropoxy)-2,4-dichlorobenzene (30 mg, 01 mmol, Acros) in toluene (500 μ) in a sealed one dram vial was heated overnight at 105 °C. The reaction was purified directly by prep HPLC (Method B) to obtain the bis TFA salt of the title compound as a yellow powder after freeze drying from dioxane overni ght (43 mg, 66% yield). XH NMR (300MHz, DMSO- d6) δ = 9.47 (br. s., 1H), 8.97 (br. s., 2H), 7.94-7.90 (m, 1H), 7.73-7.67 (m, 2H), 7.66-7.60 (m, 1H), 7.60-7.55 (m, 1H), 7.55-7.52 (m, 1H), 7.52-7.45 (m, 2H), 7.42-7.37 (m, 1H), 7.37- 7.32 (m, 1H), 7.13-7.07 (m, 1H), 4.43-4.32 (m, 2H), 4.30-4.21 (m, 2H), 4.21-4.13 (m, 2H), 3.24-3.04 (m, 6H), 2.33-2.17 (m, 2H), 2.15-1.95 (m, 2H), 1.24-1.12 (m, 6H). LCMS Method A: (M+H)+ = 525.15, 527.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.8% | With potassium carbonate In acetonitrile at 80℃; for 8h; | 7 1-bromo-3- (4 '-bromophenyl) propane 4-bromophenol (8.6g, 0 . 05mol), 1,3-dibromo propane (50g, 0.25mol), potassium carbonate (10g, 0.075mol) underwaterly to 100 ml in acetonitrile, 80 °C reaction under 8 hours. Monitoring phenol exertion end is TLC, cessation of the reaction, is placed to the room temperature, oil filtration to solid, the filtrate concentrated under reduced pressure, by adding 100 ml of chloroform, for chloroform level 0.2N two washing the sodium hydroxide aqueous solution (100 ml * 2), drying with anhydrous magnesium sulfate. Vacuum distillation, 0.4mbar pressure, taking 116-120 °C fraction, get colorless oily 9.4g, yield 64.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 24h; | 1 EXAMPLE 1 [0106] Fen-Br: N-phenyl-N-piperidin-4-yl-propionannide (Norfentanyl, 0.93 g, 4.0 mmol) and 4-bromophenethyl bromide (1.58 g, 6.0 mmol) were dissolved in 15 mL DMF, followed by addition of NN-diisopropylethylamine (0.78 g, 6.0 mmol). The reaction was kept stirring at 60 °C for 24 hours. The reaction mixture was cooled to room temperature before ethyl ether (100 mL) was added, and the organics were washed with 1 N NaOH (30 mL x 3), water (30 mL x 3) and brine (30 mL x 3). The organics were then dried over MgSC and concentrated under vacuum. The organics were redissolved in ethyl ether, and pure Fen-Br were precipitated as HC1 salt by addition of HC1 in ethanol solution (95%). NMR (500 MHz, CDC13): δ 7.41-7.35 (m, 5H), 7.08 (dd, / = 8.5, 8.5 Hz, 2H), 7.02 (d, / = 8.5 Hz, 2H), 4.68 (tt, / = 12.0, 4.0 Hz, 1H), 3.00 (d, 7 = 12.0 Hz, 2H), 2.67 (m, 2H), 2.53 (m, 2H), 1.96 (dd, / = 15.0, 7.5 Hz, 2H), 1.80 (d, / = 13.0 Hz, 2H), 1.6-1.4 (m, 4H), 1.03 (t, J = 7.5 Hz, 3H). |
95% | Stage #1: 1-bromo-4-(2-bromoethyl)benzene; Norfentanyl With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 24h; Stage #2: With hydrogenchloride In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With di-μ-iodobis(tri-t-butylphosphino)dipalladium(l) In tetrahydrofuran; toluene at 20℃; for 0.1h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With potassium carbonate In acetone at 56℃; for 18h; | 5.1.3. Representative procedure for the synthesis of final compounds General procedure: Acetone (0.5 mL) was added to phenol (4-6) (50 mg,0.144 mmol). Then K2CO3 (39.7 mg, 0.287 mmol, 2eq.) and bromide(0.144 mmol,1eq.) were added and the reaction mixturewas stirredat 56 °C overnight. Thereafter, the reaction mixture was filtered,centrifuged, and the supernatant was evaporated to dryness. Thecrude was purified using prep TLC or Biotage flash column chromatographyto afford the desired final compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.5% | at 80 - 85℃; for 4h; | 2.4 18.8g isopropanolamine added to the reaction flask, warmed to 80 ~ 85 ,Slowly add 22g brominated S2, dropping temperature during 80 ~ 85 , the dropwise addition is completed,4h after the reaction was cooled to 45 ~ 50 ° C, 80ml of water and 160ml of toluene was added,Stirred 30min liquid separation, the aqueous phase was added 40ml × 2 toluene, liquid separation, the combined organic phase was concentrated under reduced pressure,To give a light yellow solid, the light yellow solid was added to 16ml of toluene and 160ml of cyclohexane, warmed to reflux, incubated for 30min,Cool to 0 ~ 5 , and then stirred 1h, filtered, the filter cake was rinsed with 20ml of cyclohexane,The solid was dried under vacuum at 40-45 ° C to give a white solid (brominated S3): 15.6 g. Yield: 72.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | at 135℃; | 168.1 Step J. To a 100 mL round bottom flask was added 1-bromo-4-(2-bromoethyl)benzene l75a(3.5 g, 13.26 mmol, l.OO equiv.) and triethyl phosphite (10 mL). The mixture Vas heated at5 l35°C overnight with stirring. After cooling to room temperature, the mixture vasconcentrated under vacuum :md the residue was purified by silica gel columnchromatography eluting with neat petroleum ether to give diethyl [2-(4-bromophenyl)ethyl]phosphonate 175b (3.5 g, 82%) as a light yellov oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 60℃; for 1.5h; | 3 Example Compound 3: Preparation of 3-(4-bromophenethyl)-5-((7-methyl-6-oxo-6H-purin-1(7H)-yl)methyl)-1,3,4-oxadiazol-2(3H)-one The solution of 7-methyl-1-[(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-6,7-dihydro-1H-purin-6-one (~ 0.2M, 1.5 mL, prepared according to Example Compound 1 step 3) was added dropwise into a mixture of TBAI (12 mg, 0.03 mmol), Cs2C03 (222 mg, 0.68 mmol), N,N-dimethylformamide (10 mL), and l-bromo-4-(2-bromoethyl)benzene (88 mg, 0.33 mmol) at room temperature. The mixture was stirred for 1.5 h at 60°C. The reaction mixture was purified on a C18 silica gel column eluting with CH3CN/H20 (10 mmol/L NH4HC03) increasing from 5%> to 95 %> over 30 min. This resulted in the title compound (21.3 mg, 15%>) as a gray solid. LCMS [M+H+] 431. 1H NMR (400 MHz, DMSO-J6) δ 8.35 (s, 1H), 8.25 (s, 1H), 7.46 - 7.38 (m, 2H), 7.22 - 7.10 (m, 2H), 5.22 (s, 2H), 3.99 (s, 3H), 3.86 (t, J= 6.8 Hz, 2H), 2.89 (t, J= 6.8 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.8% | With pyridine In dichloromethane at 20℃; | 5 Step 3: (5-((4-Bromophenethyl)amino)-3-methylbenzofuran-2-yl)(phenyl)methanone (5-Amino-3-methylbenzofuran-2-yl)(phenyl)methanone (0.8 g, 3.65 mmol), 4-bromophenethyl bromide (1.54 g, 5.84 mmol), pyridine (1.01 g, 7.30 mmol) was added to 30 mL of dichloromethane in turn,After stirring at room temperature overnight, the pyridine was removed by water washing, and the residue was separated by column chromatography to give 1.21 g (yield 81.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; potassium iodide In acetonitrile at 40℃; Sealed tube; | General Procedure A: alkylation with potassium carbonate General procedure: Amine (0.25 mmol), and bromide (0.25 mmol) were taken up in acetonitrile (0.3 mL) in a conical vial equipped with a stirrer bar. Potassium carbonate (0.5 mmol) was added followed by potassium iodide (10 mol%) if required. The vial was sealed with a screwcap and the reaction was stirred at 40 °C until thin layer chromatography (TLC) indicated complete consumption of the starting materials. A precipitate was formed during the reaction which was removed by filtration and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography and sent to the Netherlands Cancer Institute (NKI) for biological testing. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.8 g | With potassium carbonate In acetonitrile at 20℃; for 16h; Inert atmosphere; | 1 Step 1 : tert-butyl 9-(4-bromophenethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate To a 250 ml round bottom flask were added te/ -butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (5 g, 19.7 mmol), K2C03(4.07 g, 29.5 mmol) and 1 -bromo-4-(2-bromoethyl)benzene (5.2 g, 17.6 mmol) in ACN (50 ml). The RM was stirred at RT for 16 h under N2. The RM was concentrated, diluted with water and extracted with DCM. The combined organic phases were concentrated and purified by chromatography on silica gel eluting with MeOH in DCM (1 :100) yielding the title compound as a solid (4.8 g).Method F: Rt = 1 .91 min; MS m/z [M+H]+438.1 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 60℃; for 20h; Inert atmosphere; Sealed tube; | 3-(4-Bromophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-lH-4,12- methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (72). Norhydromorphone (0.300 g, 1.11 mmol) was added to a dry round bottom flask containing a stir bar, then placed in a vaccuum oven for 2 hours. NaHC03 (0.500 g, 5.95 mmol) was added to the flask, followed by dimethylformamide (10 mL). The flask was sealed under N2, then 4-bromophenethyl bromide (0.586 g, 2.22 mmol) was added via syringe. The reaction was heated to 60 °C for 20 hours, cooled to room temperature, and filtered through a pad of celite. The DMF was removed via azeotrope with toluene (3x20 mL), then purification by Si02 column chromatography with 10% NH4OH in MeOH/CHCl3 (0% 5% of 10% NH4OH) gave 72 (0.212 g isolated, 41% yield) as a light brown oil. 1H NMR (400 MHz, CDC13): d 7.39 (d, 7 = 8.1 Hz, 2H), 7.07 (d, 7 = 8.1 Hz, 2H), 6.71 (d, 7 = 8.1 Hz, 1H), 6.58 (d, 7 = 8.1 Hz, 1H), 4.65 (s, 1H), 3.34 (d, 7 = 0.4 Hz, 1H), 2.96 (t, 7 = 15.8 Hz, 1H), 2.78-2.69 (m, 5H), 2.65-2.61 (m, 1H), 2.38-2.32 (m, 3H), 2.27-2.21 (m, 1H), 2.16-2.07 (m, 1H), 1.84-1.76 (m, 2H), 1.27-1.18 (m, 2H); 13C NMR (400 MHz, CDC13): d 209.12, 144.04, 139.08, 138.89, 131.39, 130.47, 126.78, 125.05, 120.26, 119.89, 118.00, 91.35, 57.67, 56.64, 47.40, 45.03, 42.11, 40.13, 35.16, 33.63, 25.41, 20.98; HRMS (TOF MS ES+) Calcd for C24H24BrN03 (M+H+) 454.1018, found 454.1021. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With heptamethylcobyrinate perchlorate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; N-ethyl-N,N-diisopropylamine In methanol at 45℃; for 8h; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetra-(n-butyl)ammonium iodide; caesium carbonate; Aminoiminomethanesulfinic acid; potassium iodide In dimethyl sulfoxide at 80℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium bromide In dichloromethane at 40℃; for 20h; Inert atmosphere; | Representative experimental procedure for the benzylic C-H acetoxylation by the PIDA/NaBr system General procedure: In a flame-dried two-necked round-bottomed flask, under nitrogen, phenyliodine(III) diacetate (PIDA, 193 mg, 0.6 mmol) and finely powdered sodium bromide (103 mg, 1.0 mmol) were subsequently added to a stirred solution of arylalkane 1 (0.50 mmol) and acetic acid (0.57 mL, ca. 10 mmol) in dry dichloromethane (5 mL). Then the mixture was vigorously stirred at 40 °C with or without zinc acetate (92 mg, 0.5 mmol). After checking the reaction completion by TLC, saturated aqueous sodium carbonate was added to the mixture and the resulting solution was stirred for an additional 5 min. The organic layer was separated, washed again with saturated aqueous sodium carbonate, then with dilute aqueous sodium thiosulfate, and was dried over anhydrous sodium sulfate. After removal of the solvents, the residue was subjected to column chromatography on silica gel (eluents: n-hexane/ethyl acetate) to give the benzylacetate 2 in the indicated yield; the physical and spectral data ofthe reported compounds (2a-d, g-j) matched those of the authentic samples (see Supporting Information File 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium hydrogencarbonate In N,N-dimethyl-formamide at 60℃; for 20h; | (7aR,12bS)-3-(4-Chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]-isoquinolin-7(7aH)-one (2i): General procedure: To a stirred solution of N-norhydromorphone (S10 in the SupplementaryMaterials, 0.406 g, 1.5 mmol) in DMF (10 mL) were added NaHCO3 (0.504 g, 6 mmol) and 1-(2-bromoethyl)-4-chlorobenzene (0.480 mL, 3.3 mmol). The mixture was heated at 90 °C overnight,cooled to room temperature, filtered through Celite, and concentrated in vacuo. Water (10 mL) wasadded and the mixture extracted with CHCl3 (3 × 20 mL). The combined organics were washed withH2O (5 × 20 mL), dried over Na2SO4, filtered through Celite, and concentrated in vacuo to afford 2ifree base as a crude colorless oil. Purification of this oil by SiO2 column chromatography with 10%NH4OH in MeOH/CHCl3 (gradient, 0 → 4% of 10% NH4OH) afforded 2i (0.420 g, 70%) as a colorlessoil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In tetrahydrofuran at 85℃; for 48h; | 1 Step 1: t-butyl ((exo-3-(4-bromophenethyl)-3-azabicyclo [3.1.0 ]hexan-6- yl)methyl)carbamate A mixture of 1 -bromo-4-(2-bromoethyl)benzene (0.9 g, 3.40 mmol), t-butyl ((exo-3-azabicyclo[3.1.0]hexan-6-yl)methyl)carbamate (0.7 g, 3.4 mmol), and K2CO3(1.41 mL, 10.2 mmol) in THF (10 mL) was stirred at 85 °C for 48h. It was cooled, poured into H2O (50 mL), and extracted with CH2CI2 (3x20 mL). The extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (CH3OH/CH2CI2) to afford the title compound. LCMS [M+H] 395.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; sodium iodide In acetonitrile at 70℃; | 1 Step 1: tert-butyl (1-(4-bromophenethyl)piperidin-4-yl)carbamate. To a suspension of potassium carbonate (2.10 g, 15.2 mmol), sodium iodide (0.57 g, 3.8 mmol) and 4-(N-Boc-amino)piperidine (0.76 mg, 3.8 mmol) in dry CH3CN (22 mL) at 70 °C under N2was added 1-bromo-4-(2-bromoethyl)benzene (1.0 g, 3.8 mmol) dropwise over 3 min. The reaction was stirred for 16h at 70oC, cooled and the solid was filtered. The filtrate was concentrated and purified by flash chromatography to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With potassium carbonate In acetonitrile at 80℃; for 16h; | 7.1 Step 1: Preparation of 5-[(4R,9aS)-8-[2-(4-bromophenyl)ethyl]-4-methyl-3,4,6,7,9,9a- hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 7b) A mixture of 1-bromo-4-(2-bromoethyl)benzene (compound 7a, 51.5 mg, 195 µmol), 5- [(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8- carbonitrile (Intermediate C, 40 mg, 130 µmol) and K2CO3 (54 mg, 390 µmol) in MeCN (3 mL) was stirred at 80 °C for 16 hours. Then the reaction mixture was filtered and concentrated to give compound 7b as a light yellow solid (60 mg), LCMS (M+H)+: 491 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 80℃; for 16h; | 68 Step 3: Preparation of 5-[(4R,9aS)-8-[2-(6-chloro-3-pyridyl)ethyl]-4-methyl- 3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 11d General procedure: A mixture of 2-(6-chloro-3-pyridyl)ethyl methanesulfonate (compound 11c, 173 mg, 732 µmol), 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8- carbonitrile (Intermediate C, 150 mg, 488 µmol) and potassium carbonate (202 mg, 1460 µmol,) in MeCN (10 mL) was stirred at 80 °C for 16 hours. Then the reaction was concentrated, and the residue was purified by silica gel column to give compound 11d as a light yellow solid (150 mg), LCMS (M+H)+: 447 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 80℃; for 16h; | 66 Step 3: Preparation of 5-[(4R,9aS)-8-[2-(6-chloro-3-pyridyl)ethyl]-4-methyl- 3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazin-2-yl]quinoline-8-carbonitrile (compound 11d General procedure: A mixture of 2-(6-chloro-3-pyridyl)ethyl methanesulfonate (compound 11c, 173 mg, 732 µmol), 5-[(4R,9aS)-4-methyl-1,3,4,6,7,8,9,9a-octahydropyrazino[1,2-a]pyrazin-2-yl]quinoline-8- carbonitrile (Intermediate C, 150 mg, 488 µmol) and potassium carbonate (202 mg, 1460 µmol,) in MeCN (10 mL) was stirred at 80 °C for 16 hours. Then the reaction was concentrated, and the residue was purified by silica gel column to give compound 11d as a light yellow solid (150 mg), LCMS (M+H)+: 447 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.1% | Stage #1: tabernaemontanine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In N,N-dimethyl-formamide at 20℃; | 4.1. General experimental procedures General procedure: All solvents were dried according to publish methods anddistilled prior to use. Other reagents obtained from commercialsuppliers were used without further purification. Low resolutionmass spectrometry was performed in a Triple Quadrupole massspectrometer (Micromass Quattro Micro API,Waters). NMR spectra were recorded on a Bruker 300 Ultra-Shield instrument (1H300 MHz, 13C 75 MHz). 1H and 13C NMR chemical shifts areexpressed in d (ppm), referenced to CDCl3 solvent, with the correspondingproton coupling constants (J) in Hertz (Hz). NMR spectrawere assigned using appropriate DEPT, COSY, HSQC and HMBC sequences.Column chromatography was performed on silica gel(Merck 9385). TLC were performed on precoated Merck silica gel 60F254 plates, with visualization under UV light (l 254 and 366 nm)and by spraying either with Dragendorff’s reagent or a solution ofH2SO4eMeOH (1:1), followed by heating. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.35 g | With potassium carbonate; potassium iodide In acetonitrile at 20℃; Reflux; | 4.A Step A: Preparation of 4-bromo-N-(dimethyloxido-λ4-sulfanylidene)benzeneethanamine A mixture of 1-bromo-4-(2-bromoethyl)benzene (2.50 g, 9.5 mmol), S,S-dimethyl-sulfoximine (0.98 g, 10.5 mmol), potassium carbonate (1.6 g, 11.5 mmol), potassium iodide (0.32 g, 1.9 mmol) and acetonitrile (8 mL) was heated at reflux for 18 h, cooled to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (eluting with a gradient of 10 to 100% ethyl acetate in hexanes followed by a gradient of 0 to 25% methanol in ethyl acetate) to provide the title compound as a white solid (0.35 g). 1H NMR (CDC3, 500 MHz) δ 7.40 (d, 2H), 7.11 (d, 2H), 3.28 (t, 2H), 2.92 (s, 6H), 2.81 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: Succinimide With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In N,N-dimethyl-formamide at 50℃; for 2h; Inert atmosphere; | l-[2-(4-Bromophenyl)ethyl]pyrrolidine-2,5-dione To a solution of pyrrolidine-2, 5-dione (2.24 g, 22.6 mmol) in DMF (39.5 mL) was added NaH (1.00 g, 24.9 mmol) portion wise at rt. The mixture was stirred for 60 min and a solution of l-bromo-4-(2- bromoethyl)benzene (6.59 g, 25 mmol) in DMF (13 mL) was added dropwise. The mixture was heated at 50 °C for 2 hrs and cooled in an ice-bath. EtOAc (100 mL) and brine (60 mL) were added and the mixture was stirred for 30 min and partitioned. The organic layer was washed with brine, dried over MgSC and concentrated in vacuo. The residue was slurried in TBME (40 mL) overnight. The mixture was filtered and air-dried to afford the title compound (4.78 g, 74%) as a white solid. [M+H]+ = 281.9/283.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-mercapto-indan-1-one With sodium hydride In tetrahydrofuran for 0.0833333h; Cooling with ice; Stage #2: 1-bromo-4-(2-bromoethyl)benzene In tetrahydrofuran at 20℃; for 4h; | 1.2 General procedure for the preparation of intermediates c1-c29 General procedure: A 100 mL flask was charged with b (0.3 g, 1.0 equiv) and dry THF (50 mL) on anice-water bath, then NaH (0.13 g, 3 equiv) was added in portions carefully. Fiveminutes later, bromide derivative (1.1 equiv) was added drop by drop with constantlystirring. This mixture was kept for 4 h at room temperature. And then 30 mL of waterwas added to this reaction mixture, at the same time, ethyl acetate (50 mL) was alsoadded with stirring for 5 minutes. The obtained upper layer washed with brine for 3times and dried with anhydrous magnesium sulfate. After that, the solvent was evaporated under reduced pressure and the residue was subjected to flash columnchromatography (petroleum ether as eluent) to obtain the corresponding target productc1-c29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In acetonitrile for 2h; Microwave irradiation; Heating; | 4.1.3 General method A: Preparation of compounds 4, 6, 7, 12-27 General procedure: A mixture of 11 (1 equiv.), K2CO3 (2 equiv.), and the corresponding alkyl bromide (1 equiv.) in anhydrous acetonitrile (2mL) was heated to 85°C for 2h under microwave irradiation. The white powder was filtered off, the solvent was evaporated, and the mixture was dissolved in ethyl acetate and extracted with brine. The organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The remaining crude residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/hexanes gradient) to obtain the desired compound. |
82% | With potassium carbonate In acetonitrile for 2h; Microwave irradiation; Heating; | 4.1.3 General method A: Preparation of compounds 4, 6, 7, 12-27 General procedure: A mixture of 11 (1 equiv.), K2CO3 (2 equiv.), and the corresponding alkyl bromide (1 equiv.) in anhydrous acetonitrile (2mL) was heated to 85°C for 2h under microwave irradiation. The white powder was filtered off, the solvent was evaporated, and the mixture was dissolved in ethyl acetate and extracted with brine. The organic phase was separated, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The remaining crude residue was purified by flash chromatography on silica gel (0-100% ethyl acetate/hexanes gradient) to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 52% 2: 53% | Stage #1: 2-(4-bromophenyl)-ethyl bromide; N-(2-(diphenylphosphino)-4-methoxybenzylidene)-2-methylpropan-2-amine With chromium(II) chloride In tetrahydrofuran at 20℃; for 0.0833333h; Inert atmosphere; Sealed tube; Schlenk technique; Stage #2: phenyl magensium bromide In tetrahydrofuran at 40℃; for 12h; Inert atmosphere; Sealed tube; Schlenk technique; Stage #3: With hydrogenchloride; water monomer In tetrahydrofuran at 20℃; for 3h; Schlenk technique; Inert atmosphere; Sealed tube; |
Tags: 1746-28-7 synthesis path| 1746-28-7 SDS| 1746-28-7 COA| 1746-28-7 purity| 1746-28-7 application| 1746-28-7 NMR| 1746-28-7 COA| 1746-28-7 structure
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