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CAS No. : | 836-59-9 | MDL No. : | MFCD01308572 |
Formula : | C12H16BrNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 286.17 | Pubchem ID : | - |
Synonyms : |
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Signal Word: | Class: | ||
Precautionary Statements: | UN#: | ||
Hazard Statements: | Packing Group: |
* 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 |
---|---|---|
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 65℃; for 17.5h;Industry scale;Product distribution / selectivity; | Preparation of 4-(2-(4-Bromophenoxy)ethyl)morpholine (2)[000360] A 50 L jacketed reactor equipped with a reflux condenser and temperature probe was charged with 4-(3-chloropropyl)morpholine (2.44 kg, 0.54 mol), 4-bromophenol (2.27 kg, 0.54 mol, 1.0 equiv.), powdered potassium carbonate (6.331 kg, 1.88 mol, 3.50 equiv.), and DMF (12.2 L) and stirred. The reaction mixture was then heated to 60-65 0C and stirred overnight. After 17.5 h, the reaction mixture was cooled to 20-25 0C. The reaction mixture was charged to a different reactor equipped with bottom valve for the work-up. While maintaining a temperature between 20-300C, DI water (48.7 L) was charged to the reactor. The phases were separated. The aqueous layer was extracted with MTBE (3 x 24.4 L). To the combined organics, DI water (18.3 L) and then 6M sodium hydroxide (18.2 L) <n="82"/>were added. The mixture was stirred for 2-5 minutes and the phases were separated. The organic phase was washed with water (24.4 L) and brine (24.4 L), dried over magnesium sulfate, filtered, and concentrated to give 337Og of a yellow oil (89% crude yield, 99.4% AUC by HPLC).; Step 1: Preparation of 4-(2-(4-bromophenoxy)ethyl)morpholine (2)[000343] Several modifications to the procedure described in Example 2 for the ether synthesis were developed. When conducting the ether synthesis in the acetonitnle solvent, the reaction mixture was a very thick slurry and difficult to stir. Therefore, the solvent was changed to dimethylformamide (DMF), which generated a more manageable thin white slurry. It was also determined that rigorously dry conditions were not essential. For example, 0.3 volumes of deionized (DI) water with no detrimental effects to the purity or yield of the reaction. Due to the changes in reaction solvent to DMF, the work up was also modified. The modified work up now involved dilution with DI water and extraction with <n="76"/>MTBE. It was also convenient to conduct a basic wash with aqueous sodium hydroxide to remove any remaining 4-bromophenol. |
With potassium carbonate; In water; N,N-dimethyl-formamide;Product distribution / selectivity; | Step 1: Preparation of 4-(2-(4-bromophenoxy)ethyl)morpholine (2)[000343] Several modifications to the procedure described in Example 2 for the ether synthesis were developed. When conducting the ether synthesis in the acetonitnle solvent, the reaction mixture was a very thick slurry and difficult to stir. Therefore, the solvent was changed to dimethylformamide (DMF), which generated a more manageable thin white slurry. It was also determined that rigorously dry conditions were not essential. For example, 0.3 volumes of deionized (DI) water with no detrimental effects to the purity or yield of the reaction. Due to the changes in reaction solvent to DMF, the work up was also modified. The modified work up now involved dilution with DI water and extraction with <n="76"/>MTBE. It was also convenient to conduct a basic wash with aqueous sodium hydroxide to remove any remaining 4-bromophenol. | |
With potassium carbonate; In N,N-dimethyl-formamide; | 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5) was synthesized in 3 steps. Intermediate 2 was synthesizedusing an ether coupling reaction e.g., using Williamson ether synthesis. Ether formation between 4-(2-chloroethyl)morpholine (1) and 4-bromophenol was carried out in the presence of potassium carbonate and DMF to afford 4-(2-(4-bromophenoxy)ethyl)morpholine (2). Rigorously dry conditions were not essential for this reaction and a basic washwith sodium hydroxide was used to remove any remaining 4-bromophenol. In another aspect of the invention, intermediate2 is synthesized using any ether formation reaction. Intermediate 2 is synthesized starting from compound 1 containingany leaving group. For example, the skilled chemist would start with compounds of the general formula: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate; In dimethyl sulfoxide; at 100℃; for 4.5h; | To a solution of bis-pinacolatodiboron (0.113 g, 0.44 mmol), KOAc (0.140 g, 1.45 mmol) and [1,1'-bis(diphenylphoshpino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.020 g, cat.) in DMSO (3 ML) at 100 C. was added <strong>[836-59-9]N-(4-bromophenoxyethyl)morpholine</strong> (120) (0.126 g, 0.44 mol) in DMSO (3 ML) over 30 min.After a further 4 h, the reaction mixture was cooled, diluted with ethyl acetate (50 ML), and extracted with brine (25 ML) and water (2*25 ML).The organic layer was then concentrated under reduced pressure to afford N-(4-pinacolatoboronylphenoxyethyl)morpholine (0.190 g) as a pale brown solid which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 110℃; for 17h;Inert atmosphere; | To a mixture of 2-(morpholin-4-yl)ethanol (197 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The mixture was degassed with nitrogen for 2 min and stirred at 110 C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL), washed with 2 M aqueous NaOH (3*15 mL) and brine (2*20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel to give 4-[2-(4-bromophenoxy)ethyl]morpholine (480 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.35 (d, 2H), delta 6.70 (d, 2H), 4.07 (t, 2H), 3.74-3.71 (m, 4H), 2.78 (t, 2H), 2.57-2.55 (m, 4H). |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 2.16667h; | To a solution of 4-bromophenol (3.30 g, 20.0 mmol), triphenylphoshine (5.25 g, 20.0 mmol) and N-(2-hydroxyethyl)morpholine (2.51 g, 19.1 mmol) in THF (30 ML) was added diisopropyl azodicarboxylate (3.94 ML, 20.0 mmol) over 10 min.The reaction mixture was stirred at room temperature for 2 h, and then hydrochloric acid (50 ML, 1N) was added.The mixture was extracted with diethyl ether (2*50 ML), and then the PH was adjusted to 10 with 2N aq. NaOH. The mixture was then extracted with ethyl acetate (2*50 ML) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to afford N-(4-bromophenoxyethyl)morpholine (4.54 g, 15.9 mmol) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With ammonium chloride; In tetrahydrofuran; | EXAMPLE 5 2-(p-Chorophenylmethylene)-3-[p-(2-morpholinoethoxy)phenyl]-6-methoxy-2,3-dihydrobenzo[b]furan-3-ol (5) n-Butyl lithium (2.87 mi of a 1.28M solution, 3.68 mmol) was added dropwise to a solution of <strong>[836-59-9]4-[2-morpholinoethoxy]phenyl bromide</strong> (0.80 ml, 3.68 mmol) in THF (10 ml) at -78 C. under nitrogen atmosphere. After stirring for 1 hour at -78 C., 2-(p-chlorobenzylidene)-6-methoxy-3(2H)-benzofuranone (1.0 g, 3.50 mmol) in THF (5 m was added dropwise to the mixture at -78 C. The reaction mixture was left overnight at room temperature. It was quenched with saturated ammonium chloride, THF was evaporated off to yield an oil which was extracted with ethyl acetate (2*20 ml). The ethyl acetate extract was washed with water followed by brine (2*20 ml), dried (anhydrous magnesium sulfate) and the solvent was evaporated to give an oil which was chromatographed on silica gel. Elution with (chloroform:hexane:triethylamine=1:1:0.2) yielded a solid of the free base (Rf =0.3). Yield (56%); m.p. 69-70 C.; 1H-NMR (CDCl3) delta 1.55 (brs, 1H, OH), 2.54-2.58 (m, 4H, N(CH2 CH2)20 (ring)), 2.79 (t, 2H, OCH2 CH2 N), 3.7-3.74 (m, 4H, N(CH2 CH2)2 (ring)), 3.84 (3H, OCH3), 4.09 (2H, OCH2 CH2 N), 5.64 (benzylidene proton), 6.72-7.60 (m, 11H, ArH). 13C-NMR delta(ppm) 104.4 (benzylidene carbon), 133.1 (C-2), 81.0 (C-3), 54.1 (OCH3); IR (KBr) 1680 cm-1 (C=C), 3400 cm-1 (broad OH); m/z (%) 495(5), 493(10), 100(100). (Found: C, 68.14, H, 5.89, N, 2.75, Cl, 7.30. C28H28 ClO5 N required C, 68.15, It, 5.68, N, 2.84, Cl, 7.10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; water; | In THF (100 ml) was dissolved <strong>[836-59-9]4-[2-(4-bromophenoxy)ethyl]morpholine</strong> (16.5 g). To the mixture was added dropwise at -78 C. 1.6M n-butyllithium/hexane (31.5 ml), and the mixture was stirred for 1 hour. To the mixture was added dropwise a solution of trimethyl borate (14.3 g) in THF (10 ml), and the mixture was stirred for 30 minutes and warmed to room temperature. To the mixture was added water (56 ml), and the mixture was stirred for 15 minutes. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with hexane/isopropylether to give 4-[2-(4-morpholino)ethoxy]phenyl borate (1.5 g). 1H-NMR (200 MHz, DMSO-d6) delta 2.38-2.62 (4H, m), 3.56-3.65 (6H, m), 4.10 (2H, t, J=6.2 Hz), 6.93 (2H, d, J=9.2 Hz), 7.24-7.32 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; 4-methyl-2-pentanone; | Reference Example 106 In 4-methyl-2-pentanone (96 ml) was dissolved 4-bromophenol (12 g). To the mixture were added at room temperature potassium carbonate (24 g) and 4-[2-(chloroethyl)]morpholine hydrochloride (16.9 g), and the mixture was refluxed for 18 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was filtrated to give 4-[2-(4-bromophenoxy)ethyl]morpholine (16.9 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Preparation of 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5)[000362] A 72 L reactor equipped with reflux condenser, sparging tube, bubbler, and temperature probe was charged with 6-fluoropyridin-3-ylboric acid (2.84 kg, 1.24 equiv.), 4- (2-(4-bromophenoxy)ethyl)morpholine (4.27 kg, 1.0 equiv.), and DME (27 L). Agitation was started and sodium carbonate (4.74 kg, 3.0 equiv.) as a solution in DI water (17.1 L) was then charged to the reaction mixture. Argon was bubbled through the reaction mixture for 50 minutes. Under an argon atmosphere, tetrakis(triphenylphosphine)palladium (750 g, 0.04 equiv.) was added to the reaction mixture as a slurry in DME (1.0 L). The reaction mixture was heated to 75 - 85 0C and stirred overnight (17 h). The reaction mixture was cooled to between 18 - 220C. DI water (26.681kg) and MTBE (26.681 L) were charged to the reactor and stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with MTBE (2 x 26.7 L). The combined organics were extracted with 2M HCl (1 x 15.0 L, 3 x 21.8 L). The aqueous phase was then charged back to the reactor and ethyl acetate was <n="83"/>added (26.7 L). The pH was adjusted to 6.2 using 6 M sodium hydroxide (26.7 L) while maintaining a temperature between 15 - 25 0C. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 26.7 L). The combined organics were dried with magnesium sulfate and concentrated to give 4555 g of a residue (101% crude yield, 67.1% AUC by HPLC).Purification of 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5)[000363] The crude product (575 g) was purified by silica gel chromatography by eluting with methanol/ethyl acetate/heptane (30% ethyl acetate/heptane, 50% ethyl acetate/heptane, 75% ethyl acetate/heptane, 100% ethyl acetate, and 5% methanol/ethyl acetate). Concentration of the pure fractions by TLC (10% methanol/dichloromethane, Rf = 0.3) provided 420 g of a light brown solid (73% recovery, >99.9% AUC by HPLC).; Step 3: Preparation of 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5)[000347] In performing the smaller-scale palladium coupling reactions, it was noticed that solids formed onto the glass walls of the reactor. Because the solids would act as an insulator, scaling this reaction up could result in super heating of the reactor. Two approaches were undertaken to prevent super heating. The amount of water added to the reaction was increased from 2.3 to 4.0 volumes and when the reaction was conducted on <n="77"/>kilogram scale, an additional thermo coupler between the reactor and the heating mantle was used to control the heating if a threshold temperature was met. The coupling reaction was completed in two batches, such that a total of 5269 g 4-(2-(4-Bromophenoxy)ethyl)morpholine was converted into 5735 g 4-(2-(4-(6-Fluoropyridin-3- yl)phenoxy)ethyl)morpholine, and the purity by HPLC of the batches was 94.9 and 90.3 (AUC %).Step 3a: Purification of 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5)[000348] The crude product from the palladium coupling was purified by silica gel chromatography. The material (5735 g) was purified in seven columns to give compound 5 as a light brown solid (4220 g, 97.6 AUC by HPLC), and the palladium level was 0.2 wt%. In the toxicology batch, palladium levels of 7 and 11 ppm were observed at the purified compound 5 stage. | |
68 - 100% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; H20; at 75 - 85℃; for 7.08333 - 7.83333h;Suzuki coupling;Product distribution / selectivity; | Preparation of 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5):; [000236] A 2 L three-necked round-bottomed flask equipped with mechanical stirrer, thermometer and adapter, condenser, and nitrogen inlet (at top of condenser) was charged with 2 (110.7 g, 0.387 mol), 4 (71.05 g, 0.477 mol, 1.23 eq) and DME (700 mL). The resulting stirred solution was degassed by passing a rapid stream of nitrogen through the stirred solution over a period of 5 min followed by the addition of a degassed solution of Na2CO3 (121.06 g, 1.142 mol, 3 eq) in H2O (250 mL) and also solid Pd(PPh3)4 (19.8 g, 0.044 eq). Immediately after the last addition, the head space above the reaction mixture was purged with nitrogen and the mixture then stirred at 80-85 0C (internal temperature) for 7 h, followed by cooling to room temperature. Because of the lack of an aqueous layer, the supernatant was decanted, leaving behind the inorganic salts (with adsorbed water). The reaction flask with the inorganic salts was washed with 50% dichloromethane/ethyl acetate (2 x 250 mL), the washes being added to the decanted supernatant. These combined organics were dried (Na2SO4), filtered, and evaporated to dryness to a dark brown oil (148 g). To this oil was added 150 g of 50% heptane/isopropyl alcohol (IPA) and after swirling and cooling (via ice water bath), crystallization began. Additional heptane (50 g) was added and the resulting solid was filtered, washed, and air dried to give 48 g of a light brown solid. After evaporating the filtrate to dryness, the resulting mixture was swirled in 100 mL of 50% heptane/IPA followed by the addition of more heptane (-100 mL), stoppering and placing in the freezer for crystallization. The resulting solid was filtered, washed with heptane, and air dried to give 61 g of a gummy solid. Evaporation of the resulting filtrate gave an oil (34 g) which contained significant less polar impurities including Ph3P=O and so it was partitioned between 2 N HCl (240 mL) and EtOAc (220 mL). The bottom aqueous layer was removed and then stirred with EtOAc while neutralizing with K2CO3 to a pH of 7-8. The EtOAc layer was dried, filtered, and evaporated to dryness (22 g). The 48 g, 61 g, and 22 g portions were chromato graphed over silica gel (1.1 Kg) packed in DCM. Elution with DCM (400 mL), 50% DCM/EtOAc (5 L), and then 50% DCM/EtOAc (8 L) containing increasing amounts of MeOH/Et3N (beginning with 1.5% MeOH/1% Et3N and ending with 5% MeOH/3% Et3N) gave 77.68 g of a viscous oil (purity 98.0%) which immediately crystallized upon swirling in heptane (300 mL). Filtration, washing with heptane and air drying gave 75.55 g (98.7% AUC) of solid 5. Additional pure 5 (total of 3.9 g, 98.6-99.3% AUC) was obtained from earlier chromatographic fractions containing Ph3P=O by cleaning them up as done for the above 34 g sample, followed by evaporative crystallization. The total yield of 5 was 79.5 g(68%). <n="62"/>[000237 ] 1H NMR (CDCl3) delta 2.59 (t, 4 H), 2.84 (t, 2 H), 3.75 (t, 4 H), 4.16 (t, 2 H), 6.97 (dd, 1 H), 7.01 (d, 2 H), 7.46 (d, 2 H), 7.92 (ddd, 1 H), 8.37 (fine d, 1 H). MS (from LCVMS): m/z 303.2 [M + I].; [000226] The second reaction step in the linear sequence (a Suzuki coupling) is a simple reaction to set up; all the reagents [2 (111 g), aqueous Na2CO3, DME, and Pd(PPlIa)4 (0.04 eq)] were charged to the reaction flask and the mixture heated at reflux; note that the reaction mixture was degassed to remove oxygen. Once the reaction is complete (within 7 h), the work-up involved decanting (or siphoning off) of reaction solution from the organic salts on the side of the flask (there was no visible aqueous layer), the flask was rinsed, and dried, and the solvent was removed from the combined organics. Crystallization of crude 5 from isopropanol/heptane provided material of improved purity compared to the crude, but still required chromatography (ratio of silica gel to crude was -8.5:1) to obtain material of adequate purity (>98%); the yield was 68% (79.5 g). Use of clean 5 prevented the need for chromatography in the next step, acetonitrile displacement of the fluorine atom.; Preparation of 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5) <n="68"/>[000255] A 72 L reactor equipped with reflux condenser, sparging tube, bubbler, and temperature probe was charged with 6-fluoropyridin-3-ylboric acid (2.84 kg, 1.24 equiv.), 4- (2-(4-bromophenoxy)ethyl)morpholine (4.27 kg, 1.0 equiv.), and DME (27 L). Agitation was started and sodium carbonate (4.74 kg, 3.0 equiv.) as a solution in DI water (17.1 L) was then charged to the reaction mixture. Argon was bubbled through the reaction mixture for 50 minutes. Under an argon atmosphere, tetrakis(triphenylphosphine)palladium (750 g, 0.04 equiv.) was added to the reaction mixture as a slurry in DME (1.0 L). The reaction mixture was heated to 75 - 85 0C and stirred overnight (17 h). The reaction mixture was cooled to between 18 - 22C. DI water (26.681kg) and MTBE (26.681 L) were c... |
68% | Preparation of 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5): [000326] A 2 L three-necked round-bottomed flask equipped with mechanical stirrer, thermometer and adapter, condenser, and nitrogen inlet (at top of condenser) was charged <n="69"/>with 2 (110.7 g, 0.387 mol), 4 (71.05 g, 0.477 mol, 1.23 eq) and DME (700 mL). The resulting stirred solution was degassed by passing a rapid stream of nitrogen through the stirred solution over a period of 5 min followed by the addition of a degassed solution of Na2CO3 (121.06 g, 1.142 mol, 3 eq) in H2O (250 mL) and also solid Pd(PPh3)4 (19.8 g, 0.044 eq). Immediately after the last addition, the head space above the reaction mixture was purged with nitrogen and the mixture then stirred at 80-85 0C (internal temperature) for 7 h, followed by cooling to room temperature. Because of the lack of an aqueous layer, the supernatant was decanted, leaving behind the inorganic salts (with adsorbed water). The reaction flask with the inorganic salts was washed with 50% dichloromethane/ethyl acetate (2 x 250 mL), the washes being added to the decanted supernatant. These combined organics were dried (Na2SO4), filtered, and evaporated to dryness to a dark brown oil (148 g). To this oil was added 150 g of 50% heptane/isopropyl alcohol (IPA) and after swirling and cooling (via ice water bath), crystallization began. Additional heptane (50 g) was added and the resulting solid was filtered, washed, and air dried to give 48 g of a light brown solid. After evaporating the filtrate to dryness, the resulting mixture was swirled in 100 mL of 50% heptane/IPA followed by the addition of more heptane (-100 mL), stoppering and placing in the freezer for crystallization. The resulting solid was filtered, washed with heptane, and air dried to give 61 g of a gummy solid. Evaporation of the resulting filtrate gave an oil (34 g) which contained significant less polar impurities including Ph3P=O and so it was partitioned between 2 N HCl (240 mL) and EtOAc (220 mL). The bottom aqueous layer was removed and then stirred with EtOAc while neutralizing with K2CO3 to a pH of 7-8. The EtOAc layer was dried, filtered, and evaporated to dryness (22 g). The 48 g, 61 g, and 22 g portions were chromatographed over silica gel (1.1 Kg) packed in DCM. Elution with DCM (400 mL), 50% DCM/EtOAc (5 L), and then 50% DCM/EtOAc (8 L) containing increasing amounts of MeOHTEt3N (beginning with 1.5% MeOH/1% Et3N and ending with 5% MeOH/3% Et3N) gave 77.68 g of a viscous oil (purity 98.0%) which immediately crystallized upon swirling in heptane (300 mL). Filtration, washing with heptane and air drying gave 75.55 g (98.7% AUC) of solid 5. Additional pure 5 (total of 3.9 g, 98.6-99.3% AUC) was obtained from earlier chromatographic fractions containing Ph3P=O by cleaning them up as done for the above 34 g sample, followed by evaporative crystallization. The total yield of 5 was 79.5 g (68%).[000327] 1H NMR (CDCl3) delta 2.59 (t, 4 H), 2.84 (t, 2 H), 3.75 (t, 4 H), 4.16 (t, 2 H), 6.97 (dd, 1 H), 7.01 (d, 2 H), 7.46 (d, 2 H), 7.92 (ddd, 1 H), 8.37 (fine d, 1 H). MS (from LC/MS): /w/z 303.2 [M + l]. ; [000316] The second reaction step in the linear sequence (a Suzuki coupling) is a simple reaction to set up; all the reagents [2 (111 g), aqueous Na2CO3, DME, and Pd(PPh3)4 (0.04 eq)] were charged to the reaction flask and the mixture heated at reflux; note that the reaction mixture was degassed to remove oxygen. Once the reaction is complete (within 7 h), the work-up involved decanting (or siphoning off) of reaction solution from the organic salts on the side of the flask (there was no visible aqueous layer), the flask was rinsed, and dried, and the solvent was removed from the combined organics. Crystallization of crude 5 from isopropanol/heptane provided material of improved purity compared to the crude, but still required chromatography (ratio of silica gel to crude was ~8.5: 1) to obtain material of adequate purity (>98%); the yield was 68% (79.5 g). Use of clean 5 prevented the need for chromatography in the next step, acetonitrile displacement of the fluorine atom |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; | Compound 5 was formed using a Suzuki reaction. Formation of the aryl borate, 6-fluoropyridin-3-yl-3-boronicacid (4), was carried out by forming the aryl anion using n-BuLi followed by in situ quenching with triisopropylborate (Li,et al., J. Org. Chem. 2002, 67, 5394-5397). The resulting 6-fluoropyridin-3-yl-3-boronic acid (4) was coupled to <strong>[836-59-9]4-(2-(4-bromophenoxy)ethyl)morpholine</strong> (2) in a solution of DME and aqueous sodium carbonate using tetrakis(triphenylphosphine)palladium to afford 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine (5), which was purified using silica gelchromatography. The skilled chemist would know that other transition metal coupling reaction are used to preparecompound 5 |
Yield | Reaction Conditions | Operation in experiment |
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100% | With potassium carbonate; In acetonitrile; at 80℃;Product distribution / selectivity; | Preparation of 4-(2-(4-bromophenoxy)ethyl)morpholine (2):; [000231] A 5 L three-necked round-bottomed flask, equipped with mechanical stirrer, thermometer with adapter, condenser, and nitrogen inlet (on top of condenser), was charged with 1 (140.7 g, 0.756 mol), 4-bromophenol (130.6 g, 0.755 mol), anhydrous K2CO3 powder (367.6 g, 2.66 mol, 3.5 eq), and acetonitrile (1.3 L). The mixture was vigorously stirred (blade touching bottom of flask) at 80 0C (overnight), followed by dilution with DCM (500 mL) and heptane (200 mL) and filtration through Celite. Evaporation to dryness (rotovap, then high vac) gave 2 as a light yellow oil (216.00 g, yield of 100%, 96.3% AUC, contains 3.7% unreacted bromophenol). This material was used successfully without further purification.[000232 ] 1H NMR (CDCl3) delta 2.57 (t, 4 H), 2.79 (t, 2 H), 3.73 (t, 4 H), 4.08 (t, 2 H), 6.78 (d, 2 H), 7.37 (d, 2 H). MS (from LC/MS): m/z 287.1 [M + I].; [000224 ] The first step is a Williamson ether synthesis between 4-bromophenol (131 g) and N-chloroethylmorpholine (1 as the HCl salt; 141 g) using K2CO3 powder (3 to 3.5 equivalents) as the base and having acetonitrile as the solvent. The ingredients were mixed and stirred at reflux overnight with high conversion (96.3-99.1%). After dilution with dichloromethane and heptane, the reaction mixture was filtered and evaporated to give the desired product 2 in essentially a quantitative yield (216 g). Note that with similar substrates (e.g., 4-bromo-3-fluorophenol), conversions (even with extensive heating) were not always so high (e.g., 59.9-98.3%). Both the alkyl chloride and the K2CO3 are preferably purchased from Aldrich. If continued heating does not drive reaction to completion, unreacted bromophenol can readily be removed by dissolving the crude reaction mixture in 4 parts toluene and washing out the phenol with 4 parts 15% aqueous NaOH. |
100% | With potassium carbonate; In acetonitrile; at 80℃;Product distribution / selectivity; | Preparation of 4-(2-(4-bromophenoxy)ethyl)morpholine (2):[000321] A 5 L three-necked round-bottomed flask, equipped with mechanical stirrer, thermometer with adapter, condenser, and nitrogen inlet (on top of condenser), was charged with 1 (140.7 g, 0.756 mol), 4-bromophenol (130.6 g, 0.755 mol), anhydrous K2CO3 powder(367.6 g, 2.66 mol, 3.5 eq), and acetonitrile (1.3 L). The mixture was vigorously stirred(blade touching bottom of flask) at 800C (overnight), followed by dilution with DCM (500 mL) and heptane (200 mL) and filtration through Celite. Evaporation to dryness (rotovap, then high vac) gave 2 as a light yellow oil (216.00 g, yield of 100%, 96.3% AUC, contains3.7% unreacted bromophenol). This material was used successfully without further purification.[000322] 1H NMR (CDCl3) delta 2.57 (t, 4 H), 2.79 (t, 2 H), 3.73 (t, 4 H), 4.08 (t, 2 H), 6.78(d, 2 H), 7.37 (d, 2 H). MS (from LC/MS): m/z 287.1 [M + I].; [000314] The first step is a Williamson ether synthesis between 4-bromophenol (131 g) and N-chloroethylmorpholine Q. as the HCl salt; 141 g) using K2CO3 powder (3 to 3.5 equivalents) as the base and having acetonitrile as the solvent. The ingredients were mixed and stirred at reflux overnight with high conversion (96.3-99.1%). After dilution with dichloromethane and heptane, the reaction mixture was filtered and evaporated to give the desired product 2 in essentially a quantitative yield (216 g). Note that with similar substrates (e.g., 4-bromo-3-fluorophenol), conversions (even with extensive heating) were not always so <n="65"/>high (e.g., 59.9-98.3%). Both the alkyl chloride and the K2CO3 are preferably purchased from Aldrich. If continued heating does not drive reaction to completion, unreacted bromophenol can readily be removed by dissolving the crude reaction mixture in 4 parts toluene and washing out the phenol with 4 parts 15% aqueous NaOH. |
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 65℃; for 17.5h;Product distribution / selectivity; | Preparation of 4-(2-(4-Bromophenoxy)ethyl)morpholine (2); [000253 ] A 50 L jacketed reactor equipped with a reflux condenser and temperature probe was charged with 4-(3-chloropropyl)morpholine (2.44 kg, 0.54 mol), 4-bromophenol (2.27 kg, 0.54 mol, 1.0 equiv.), powdered potassium carbonate (6.331 kg, 1.88 mol, 3.50 equiv.), and DMF (12.2 L) and stirred. The reaction mixture was then heated to 60-65 0C and stirred overnight. After 17.5 h, the reaction mixture was cooled to 20-25 C. The reaction mixture was charged to a different reactor equipped with bottom valve for the work-up. While maintaining a temperature between 20-30 0C, DI water (48.7 L) was charged to the reactor. The phases were separated. The aqueous layer was extracted with MTBE (3 x 24.4 L). To the combined organics, DI water (18.3 L) and then 6M sodium hydroxide (18.2 L) were added. The mixture was stirred for 2-5 minutes and the phases were separated. The organic phase was washed with water (24.4 L) and brine (24.4 L), dried over magnesium sulfate, filtered, and concentrated to give 337Og of a yellow oil (89% crude yield, 99.4% AUC by HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 1h;Inert atmosphere; Microwave irradiation; | To a solution of <strong>[836-59-9]4-[2-(4-bromophenoxy)ethyl]morpholine</strong> (498 mg, 1.74 mmol) in 1,4-dioxane (10 mL) was added 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (431 mg, 1.91 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (124 mg, 0.174 mmol) and KOAc (0.853 g, 8.7 mmol). The mixture was degassed with nitrogen for 3 min and heated to 110 C. by microwave irradiation for 1 h. The mixture was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL) and washed with brine (2*15 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography to give 4-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethyl}morpholine (190 mg, 34%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | Stage #1: 1-bromo-4-(2-morpholinoethoxy)benzene With n-butyllithium; magnesium chloride In tetrahydrofuran at -10 - -5℃; for 1h; Stage #2: 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at -10 - 0℃; for 5.5h; | 1-2 Example 2 The present embodiment provides a method for synthesizing tirbanibulin intermediate, the synthesis process is as follows: At -10 °C, n-butyllithium (2.5 mol/L, 46 mL) was slowly added dropwise to a solution of magnesium chloride (10.9 g) in tetrahydrofuran (150 mL), and the reaction was stirred for 1.5 hours at this temperature. A solution of 1 (4-[2-(4-bromophenoxy)ethyl]morpholine) (28.6g) in tetrahydrofuran (50mL) was added dropwise to the above reaction, and the reaction temperature was controlled at -10°C - -5°C in between, and then the reaction was stirred for an additional hour. Finally, raw material 2 (isopropoxyboronic acid pinacol ester) (20.5 g) was added, and after the addition, the temperature was slowly raised to 0° C, and the stirring reaction was continued for 5.5 hours. After monitoring the completion of the reaction, 250 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, followed by extraction with 250 mL of ethyl acetate, and the organic phase was collected, dried, and spin-dried. The obtained crude product was recrystallized from an ethanol/water mixed solution to obtain 32.3 g of tirbanibulin intermediate with a yield of 96.7% and a HPLC purity of 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.1 % | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 90℃; Inert atmosphere; | 1.4; 2.4 4) Synthesis of tenibulin Measure 1216ml DMSO and add to the reaction flask; weigh 140.9g of formula 4 and add to the reaction flask, stir; weigh 114g of formula 7 and add to the reaction flask, weigh 98g of potassium acetate and stir into the reaction flask, nitrogen replacement 3 times; quickly add 6.1 grams of PdCl2 ( dppf), stirred, replaced with nitrogen 3 times, heated to 90°C, and reacted for 12h. Cool down to room temperature, add 930ml of tap water and stir; add 930ml of ethyl acetate and stir for 5 minutes, separate the layers, extract the aqueous layer twice with ethyl acetate (930ml*2), combine the organic layers; evaporate the solvent under reduced pressure and then chromatographically purify. Add 135 g of the purified tenibulin crude product into the reaction flask, add 5400 mL of tetrahydrofuran, and heat to dissolve. 3037 mL of n-heptane was added dropwise. Cool down to room temperature after dropping, filter with suction, and wash the filter cake with THF/n-heptane = 1:4. Dry the filter cake under reduced pressure at a temperature of 45-55°C. Add 115 g of dried tenibulin primary crude product into the reaction flask, add 4600 m of ethyl acetate, heat to 55 ° C, dissolve completely, and stir for 30 min. Lower the internal temperature to 45°C, stir and crystallize for 2h. Lower the internal temperature to -5°C and stir for 3h. Suction filtration, the filter cake was washed twice with ethyl acetate pre-cooled at -5°C, and the filter cake was dried under reduced pressure at a temperature of 45 to 55°C to a constant weight to obtain 95g of tenibulin (Figure 1), |
Tags: 836-59-9 synthesis path| 836-59-9 SDS| 836-59-9 COA| 836-59-9 purity| 836-59-9 application| 836-59-9 NMR| 836-59-9 COA| 836-59-9 structure
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