* 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.
With potassium carbonate In ethanol for 4 h; Reflux
To a suspension of m-bromophenol (1) (15.57 g, 90 mmol) in dehydrated alcohol (300 mL) was added anhydrous potassium carbonate (37.32 g, 270 mmol) and benzyl chloride (11.50 mL, 99 mmol). The mixture was refluxed for 4 h. Filtration and evaporation of alcohol was done in a vacuum. The residue was extracted with EtOAc. The combined organic layers were washed with water, NaOH (2 M), brine, and HCl (2 M), dried over Na2SO4, and concentrated to give (2) (22.02 g, 93percent) as a yellow solid. A 250 mL, two-necked, round-bottomed flask containing dry magnesium (2.18 g, 90 mmol) and iodine (trace) was equipped with two rubber septum stirred under the protection of nitrogen. The solution of (2) (15.79 g, 60 mmol) in 40 mL of anhydrous THF was added slowly into the flask through a syringe at a rate to remain reflux. After addition finishing, the resulting mixture was kept in refluxing for 5 h with stirring. The mixture in cooled to -30 °C, then the trimethylborate (9.36 g, 90 mmol) in 60 mL of anhydrous THF was added slowly through a syringe. After addition finishing, the resulting mixture was allowed to stir at room temperature for overnight and then treated with saturated NH4Cl solution, stirred for 1 h at room temperature. Then THF was removed by rotary evaporation. The aqueous layer was extracted with EtOAc and dried over Na2SO4, filtered and concentrated to afford the yellow crude product. The crude product was purified by recrystallization from water affording (3) as a white solid (7.53 g, 55percent).
1.6 g
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2 h;
(1) 0.77 g of benzyl chloride was dropwise added to a mixed solution comprising 1.0 g of 3-bromophenol, 1.6 g of potassium carbonate and 5 mL of N,N- dimethylformamide. After completion of the dropwise addition, a reaction was carried out at 60°C for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and an aqueous sodium chloride solution, and anhydrous sodium sulfate was added for drying. The solvent was distilled off under reduced pressure to obtain 1.6 g of oily 1 - (benzyloxy)-3-brornobenzene.
Reference：
[1] Journal of Materials Chemistry, 2010, vol. 20, # 15, p. 3069 - 3078
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1044 - 1054
[3] Journal of Medicinal and Pharmaceutical Chemistry, 1962, vol. 5, p. 752 - 762
[4] Patent: US5447656, 1995, A,
[5] Patent: EP838461, 1998, A2,
[6] Patent: US2007/209123, 2007, A1, . Location in patent: Page/Page column 8
[7] Patent: WO2013/27660, 2013, A1, . Location in patent: Page/Page column 21
[8] Macromolecules, 2016, vol. 49, # 10, p. 3706 - 3715
[9] Patent: CN104016879, 2016, B, . Location in patent: Paragraph 0045; 0046
[10] Patent: CN103980153, 2016, B, . Location in patent: Paragraph 0048; 0049; 0050
2
[ 591-20-8 ]
[ 100-39-0 ]
[ 53087-13-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In acetone for 15 h; Reflux
A solution of 3-bromophenol (3 g, 17.34 mmol) in acetone (100 mL) was added with benzyl bromide (2.2 mL, 19.07 mmol) and K2CO3 (7.0 g, 52.02 mmol), and the resulting mixture was refluxed for 15 hours. The reaction mixture was cooled to room temperature, filtered, and washed with acetone. The filtrate was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 5.1 g, 100percent yield). 1H NMR (300 MHz, CDCl3) δ 7.50 - 7.30 (m, 5H), 7.20 - 7.01 (m, 3H), 6.98 - 6.80 (m, 1H), 5.05 (s, 2H).
96%
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 20 h;
Example 81 3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid Step A 3-Benzyloxy-1-bromobenzene A mixture of 3-bromophenol (10. 0 g, 57.8 mmol) and 325 mesh potassium carbonate (8.79 g, 63.6 mmol) in DMF (100 mL) is treated dropwise with benzyl bromide (9.89 g, 57.8 mmol) and then stirred 20 hours at rt under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCI. The mixture is then diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/ethyl acetate to afford 14.55 g (96percent) of the titled compound. Rf= 0.86 (4/1 hexanes/EtOAc). IH NMR (400 MHz, CDC13).
79%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12 h;
Step-1: Synthesis of l-(benzyloxy)-3-bromobenzene BnBr/K2C03 DMF HO Br RT/12 h BnO Br To a solution of 3-bromophenol (5 g, 28.9 mmol)' in DMF (50 mL), were added potassium carbonate (11.9 g, 86.7 mmol) and benzyl bromide (5.9 g, 34.6 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04i concentrated under reduced pressure. The crude compound was purified over 230- 400 mesh silica gel column chromatography using 8percent EtOAc in n-hexane to afford 1- (benzyloxy)-3-bromobenzene (6 g, 79percent).
67%
With potassium carbonate In hexane; dichloromethane; water; acetone
4.6.2.19 3-(3-Benzyloxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile To a stirred solution of bromomethylbenzene (24.39 g, 143 mmol), 3-bromophenol (24.92 g, 144 mmol) in acetone (20 ml) was added potassium carbonate (59.72 g, 430 mmol). The suspension was refluxed overnight and then evaporated. To the residue was added H2O (100 ml) and extracted with EtOAc (3*80 ml). The combined EtOAc extracts were back washed with Na2CO3 and then dried over MgSO4, filtered and evaporated to get an off-white solid, which was purified via flash column chromatography (10percent CH2Cl2 in hexane) to give 1-benzyloxy-3-bromo-benzene as a white solid (10 g, 67percent): 1H-NMR (DMSO-d6) 7.46-7.00 (m, 9H, Ar), 5.12 (s, 2H, CH2). The product was carried over to the next step.
67%
With potassium carbonate In water; acetone
4.6.2.95 (E/Z)-3-(3,5-Dimethoxy-phenyl)-3-(3-ethoxy-phenyl)-acrylonitrile To a stirred solution of benzyl bromide (24.39 g, 142.6 mmol) and 3-bromo phenol (24.92 g, 144 mmol) in 20 mL of fresh acetone was added potassium carbonate (59.72 g, 432 mmol). The suspension was refluxed overnight. The mixture was evaporated and added water (100 mL), extracted with EtOAc (3*80 mL). The combined EtOAc extracts were back washed with water (100 mL), dried over MgSO4, filtered and evaporated to give 1-benzyloxy-3-bromo-benzene as an off-white solid (10.0 g, 67percent yield): 1H NMR (DMSO-d6) δ 5.12 (s, 2H, CH2), 7.00-7.46 (m, 9H, Ar).
67%
With potassium carbonate In water; acetone
4.6.2.96 Z-3-(3,5-Dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-acrylonitrile To a stirred solution of benzyl bromide (24.39 g, 142.6 mmol) and 3-bromo phenol (24.92 g, 144 mmol) in 20 mL of fresh acetone was added potassium carbonate (59.72 g, 432 mmol). The suspension was refluxed overnight. The mixture was evaporated and added water (100 mL), extracted with EtOAc (3*80 mL). The combined EtOAc extracts were back washed with water (100 mL), dried over MgSO4, filtered and evaporated to give 1-benzyloxy-3-bromo-benzene as an off-white solid (10.0 g, 67percent yield): 1H NMR (DMSO-d6) δ 5.12 (s, 2H, CH2), 7.00-7.46 (m, 9H, Ar).
59%
With potassium carbonate In acetone for 3 h; Heating / reflux
REFERENCE EXAMPLE 1 3-(Benzyloxy)bromobenzene 3-Bromophenol (50 g, 0.289 mol) was dissolved in acetone (500 ml), anhydrous potassium carbonate (80 g, 0.580 mmol) and benzyl bromide (59 g, 0.345 mol) were successively added thereto and the mixture was heated to reflux for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting crude reaction product was recrystallized (hexane was used as a solvent and the recrystallization operation was carried out twice) to give the title compound (45.0 g, 0.171 mol, 59percent).
57%
With potassium carbonate In acetone for 4 h; Reflux
Intermediate 21 : 1-(benzyloxy)-3-bromobenzene A mixture of 3-bromophenol (2.60 g, 1.59 mL, 15 mmol), benzyl bromide (2.82 g 1.96 mL, 16.5 mmol) and potassium carbonate (2.07 g, 15 mmol) in acetone (25 mL) was refluxed for 4 hours. The reaction mixture was cooled to room temperature. The mixture was filtered and the solvent was evaporated from the filtrate. The residue was purified by chromatography on silica gel eluting with 0- 25 percent ethyl acetate/hexane. Appropriate fractions were combined and evaporated. The impure product was re-purified by chromatography on silica gel eluting with 0-10 percent ethyl acetate/hexane to give 1-(benzyloxy)-3-bromobenzene (2.25 g, 8.55 mmol, 57.0 percent yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ-ppm 7.46-7.32 (m, 5H), 7.27-7.22 (m, 2H), 7.13 (m,1 H), 7.03 (m,
26 g
With potassium carbonate In acetone for 2 h; Reflux
To a mixture of 3-bromophenol (20 g, 0.115 mol) and potassium carbonate (95 g, 0.69 mol, 6 eq) in acetone (500 ml) was added benzyl bromide (15.12 ml, 0.127 mol, 1.1 eq). The reaction mixture was heated at reflux for 2 hours (TLC showed completion of reaction). The reaction mixture was filtered, washed with acetone and the filtrate was evaporated to dryness. The residue was dissolved in water (200 ml) and ethyl acetate (200 ml). The layers were separated. The organic layer was washed with brine (200 ml), dried over sodium sulfate, filtered and evaporated to dryness. The crude was recrystallized from hexane to give the title compound (26 g) 3 as a white solid. MP 61-62° C.
With potassium carbonate; In ethanol; for 4h;Reflux;
To a suspension of m-bromophenol (1) (15.57 g, 90 mmol) in dehydrated alcohol (300 mL) was added anhydrous potassium carbonate (37.32 g, 270 mmol) and benzyl chloride (11.50 mL, 99 mmol). The mixture was refluxed for 4 h. Filtration and evaporation of alcohol was done in a vacuum. The residue was extracted with EtOAc. The combined organic layers were washed with water, NaOH (2 M), brine, and HCl (2 M), dried over Na2SO4, and concentrated to give (2) (22.02 g, 93percent) as a yellow solid. A 250 mL, two-necked, round-bottomed flask containing dry magnesium (2.18 g, 90 mmol) and iodine (trace) was equipped with two rubber septum stirred under the protection of nitrogen. The solution of (2) (15.79 g, 60 mmol) in 40 mL of anhydrous THF was added slowly into the flask through a syringe at a rate to remain reflux. After addition finishing, the resulting mixture was kept in refluxing for 5 h with stirring. The mixture in cooled to -30 °C, then the trimethylborate (9.36 g, 90 mmol) in 60 mL of anhydrous THF was added slowly through a syringe. After addition finishing, the resulting mixture was allowed to stir at room temperature for overnight and then treated with saturated NH4Cl solution, stirred for 1 h at room temperature. Then THF was removed by rotary evaporation. The aqueous layer was extracted with EtOAc and dried over Na2SO4, filtered and concentrated to afford the yellow crude product. The crude product was purified by recrystallization from water affording (3) as a white solid (7.53 g, 55percent).
In N-methyl-acetamide; water; isopropyl alcohol; mineral oil;
EXAMPLE 1 2-(3-Methoxyphenyl)-5-(4-octyloxyphenyl), pyrimidine: 25.43 g (0.64 mol) of a 60percent strength by weight sodium hydride dispersion in mineral oil are added in portions at room temperature to 100 g (0.58 mol) of commercially available 3-bromophenol in 600 ml of dimethylformamide, the mixture is stirred for a further half an hour, and 66.5 ml (0.58 mol) of commercially available benzyl chloride are added dropwise. The mixture is stirred at room temperature for 1 hour, 11 of water is added, and the solid which precipitates is filtered off, washed with water and recrystallized from 600 ml of isopropanol, giving 108 g of 3-benzyloxybromobenzene. STR12
In N,N-dimethyl-formamide;
Preparation 2 3-Benzyloxy-bromobenzene A slurry of 3-bromophenol 100g (580 mmol), benzylchloride 80g (700 mmol), and K2CO3168g (1210 mmol) in 2 L of DMF was stirred for sixteen hour at ambient temperature. The reaction mixture was filtered and evaporated to dryness. The solid was partioned between CHCl3and water. The organic layer was separated, washed twice with brine, and dried by filtration through anhydrous Na2SO4. The solution was evaporated to dryness. This yielded 142.5 g of the title compound as a white solid. PMR: Consistent with the proposed structure MS: 262 and 264 (M+) FD EA: Calc: C, 59.34; H, 4.21 Found: C, 59.59; H, 4.17 C13H11BrO
With potassium carbonate; In N,N-dimethyl-formamide;
Benzylation of 3-bromophenol 1 with benzyl chloride and potassium carbonate in DMF affords compound 2. Palladium (0)-catalyzed cross-coupling reaction of 2 with bis(pinacolato)diboron, PdCl2(dppf), and potassium carbonate in DMSO at 80° C. gives rise to compound 3 (Ishiyama, T; Murata, M; Miyaura, N. J. Org. Chem. 1995, 60, 7508). Debenzylation of 3 with Pd/C at 60 psi hydrogen in MeOH produces the target compound 4 (Pennington, T. E.; Kardiman, C; Hutton, C. A. Tetrahedron Lett. 2004, 45, 6657).
1.6 g
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;
(1) 0.77 g of benzyl chloride was dropwise added to a mixed solution comprising 1.0 g of 3-bromophenol, 1.6 g of potassium carbonate and 5 mL of N,N- dimethylformamide. After completion of the dropwise addition, a reaction was carried out at 60°C for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and an aqueous sodium chloride solution, and anhydrous sodium sulfate was added for drying. The solvent was distilled off under reduced pressure to obtain 1.6 g of oily 1 - (benzyloxy)-3-brornobenzene.
1) 3-bromophenol (1) undergoes benzylation reaction to prepare compound 1-benzyloxy-3-bromobenzene (2)15.57g (90mmol) 3- bromophenol (1) was dissolved in 300mL anhydrous ethanol, was added 37.32g (270mmol) of anhydrous potassium carbonate,stirred at room temperature for ten minutes, then add 11.50mL (99mmol) benzylchloride, was heated under reflux for 5 hours. After the reaction is finished, and cooling to room temperature, ethanol recovery filtrate under reduced pressure, then adding ethyl acetate extraction, the organic phase with dilute hydrochloric acid,water, saturated sodium bicarbonate solution, water, saturated sodium chloride solution, the final organic phase after drying with anhydrous sodium sulfate the solvent evaporate under reduced pressure, to obtain pale yellow 1-benzyloxy-3-bromobenzenecrude product (2)22.02g, yield 93percent.
15.57 g (90 mmol) of 3-bromophenol (1)Dissolved in 300ml of anhydrous ethanol,37.32 g (270 mmol) of anhydrous potassium carbonate was added,Stirred at room temperature for ten minutes,Further, 11.50 ml (99 mmol) of benzyl chloride was added,The mixture was heated under reflux for 5 hours.After completion of the reaction,Cooled to room temperature suction filtration,The filtrate was decompressed to recover ethanol,Then extracted with ethyl acetate,The organic phase was washed with dilute hydrochloric acid,water,Saturated sodium bicarbonate solution,water,Saturated sodium chloride solution,Finally, the organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure.To give pale yellow 1-benzyloxy-3-bromobenzene (2)Crude 22.02 g,Yield 93percent.
Step A (3-Benzyloxyphenyl)(3-chlorophenyl)methanol To a stirred suspension of Rieke Mg (0.93 g, 38 mmol) in refluxing dry THF (15 mL), under argon, was added benzyl 3-bromophenyl ether as described in Example 7, Step A, (9.0 g, 34 mmol) in dry THF (90 mL) dropwise, at a rate that maintained reflux with the heat source removed. The resulting mixture was heated to reflux for 1 hour, then allowed to cool to ambient temperature. The solution of Grignard reagent was added dropwise to a stirred solution of 3-chlorobenzaldehyde in THF (50 mL) at -78° C. The reaction mixture was stirred at -78° C. for 1 hour, then quenched with saturated aqueous NH4Cl (200 mL), allowed to warm to ambient temperature, and extracted with Et2O (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluding with hexane-7percent EtOAc, to yield the titled product as a colorless oil.
With potassium carbonate; In acetone; for 15h;Reflux;
A solution of 3-bromophenol (3 g, 17.34 mmol) in acetone (100 mL) was added with benzyl bromide (2.2 mL, 19.07 mmol) and K2CO3 (7.0 g, 52.02 mmol), and the resulting mixture was refluxed for 15 hours. The reaction mixture was cooled to room temperature, filtered, and washed with acetone. The filtrate was concentrated and purified by silica gel chromatography to obtain the title compound (white solid, 5.1 g, 100% yield). 1H NMR (300 MHz, CDCl3) delta 7.50 - 7.30 (m, 5H), 7.20 - 7.01 (m, 3H), 6.98 - 6.80 (m, 1H), 5.05 (s, 2H).
98%
With potassium carbonate; In ethanol; at 70℃; for 6h;
60101 (492.0) was dissolved in absolute ethanol (5 L),Add benzyl bromide (535.0),Anhydrous potassium carbonate (1179.1 g).The reaction was stirred at 70 C for 6 h.Pour into the water,filter,The filter cake is washed 3 times and dried to obtain 734 g of product;Purity: 97%,Yield: 98%.
96%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 20h;Product distribution / selectivity;
Example 81 3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid Step A 3-Benzyloxy-1-bromobenzene A mixture of 3-bromophenol (10. 0 g, 57.8 mmol) and 325 mesh potassium carbonate (8.79 g, 63.6 mmol) in DMF (100 mL) is treated dropwise with benzyl bromide (9.89 g, 57.8 mmol) and then stirred 20 hours at rt under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCI. The mixture is then diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/ethyl acetate to afford 14.55 g (96%) of the titled compound. Rf= 0.86 (4/1 hexanes/EtOAc). IH NMR (400 MHz, CDC13).
79%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
Step-1: Synthesis of l-(benzyloxy)-3-bromobenzene BnBr/K2C03 DMF HO Br RT/12 h BnO Br To a solution of 3-bromophenol (5 g, 28.9 mmol)' in DMF (50 mL), were added potassium carbonate (11.9 g, 86.7 mmol) and benzyl bromide (5.9 g, 34.6 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04i concentrated under reduced pressure. The crude compound was purified over 230- 400 mesh silica gel column chromatography using 8% EtOAc in n-hexane to afford 1- (benzyloxy)-3-bromobenzene (6 g, 79%).
67%
With potassium carbonate; In hexane; dichloromethane; water; acetone;
4.6.2.19 3-(3-Benzyloxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylonitrile To a stirred solution of bromomethylbenzene (24.39 g, 143 mmol), 3-bromophenol (24.92 g, 144 mmol) in acetone (20 ml) was added potassium carbonate (59.72 g, 430 mmol). The suspension was refluxed overnight and then evaporated. To the residue was added H2O (100 ml) and extracted with EtOAc (3*80 ml). The combined EtOAc extracts were back washed with Na2CO3 and then dried over MgSO4, filtered and evaporated to get an off-white solid, which was purified via flash column chromatography (10% CH2Cl2 in hexane) to give 1-benzyloxy-3-bromo-benzene as a white solid (10 g, 67%): 1H-NMR (DMSO-d6) 7.46-7.00 (m, 9H, Ar), 5.12 (s, 2H, CH2). The product was carried over to the next step.
67%
With potassium carbonate; In water; acetone;
4.6.2.95 (E/Z)-3-(3,5-Dimethoxy-phenyl)-3-(3-ethoxy-phenyl)-acrylonitrile To a stirred solution of benzyl bromide (24.39 g, 142.6 mmol) and 3-bromo phenol (24.92 g, 144 mmol) in 20 mL of fresh acetone was added potassium carbonate (59.72 g, 432 mmol). The suspension was refluxed overnight. The mixture was evaporated and added water (100 mL), extracted with EtOAc (3*80 mL). The combined EtOAc extracts were back washed with water (100 mL), dried over MgSO4, filtered and evaporated to give 1-benzyloxy-3-bromo-benzene as an off-white solid (10.0 g, 67% yield): 1H NMR (DMSO-d6) delta 5.12 (s, 2H, CH2), 7.00-7.46 (m, 9H, Ar).
67%
With potassium carbonate; In water; acetone;
4.6.2.96 Z-3-(3,5-Dimethoxy-phenyl)-3-(3-hydroxy-phenyl)-acrylonitrile To a stirred solution of benzyl bromide (24.39 g, 142.6 mmol) and 3-bromo phenol (24.92 g, 144 mmol) in 20 mL of fresh acetone was added potassium carbonate (59.72 g, 432 mmol). The suspension was refluxed overnight. The mixture was evaporated and added water (100 mL), extracted with EtOAc (3*80 mL). The combined EtOAc extracts were back washed with water (100 mL), dried over MgSO4, filtered and evaporated to give 1-benzyloxy-3-bromo-benzene as an off-white solid (10.0 g, 67% yield): 1H NMR (DMSO-d6) delta 5.12 (s, 2H, CH2), 7.00-7.46 (m, 9H, Ar).
59%
With potassium carbonate; In acetone; for 3h;Heating / reflux;
REFERENCE EXAMPLE 1 3-(Benzyloxy)bromobenzene 3-Bromophenol (50 g, 0.289 mol) was dissolved in acetone (500 ml), anhydrous potassium carbonate (80 g, 0.580 mmol) and benzyl bromide (59 g, 0.345 mol) were successively added thereto and the mixture was heated to reflux for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting crude reaction product was recrystallized (hexane was used as a solvent and the recrystallization operation was carried out twice) to give the title compound (45.0 g, 0.171 mol, 59%).
57%
With potassium carbonate; In acetone; for 4h;Reflux;
Intermediate 21 : 1-(benzyloxy)-3-bromobenzene A mixture of 3-bromophenol (2.60 g, 1.59 mL, 15 mmol), benzyl bromide (2.82 g 1.96 mL, 16.5 mmol) and potassium carbonate (2.07 g, 15 mmol) in acetone (25 mL) was refluxed for 4 hours. The reaction mixture was cooled to room temperature. The mixture was filtered and the solvent was evaporated from the filtrate. The residue was purified by chromatography on silica gel eluting with 0- 25 % ethyl acetate/hexane. Appropriate fractions were combined and evaporated. The impure product was re-purified by chromatography on silica gel eluting with 0-10 % ethyl acetate/hexane to give 1-(benzyloxy)-3-bromobenzene (2.25 g, 8.55 mmol, 57.0 % yield) as a white solid. 1H NMR (400MHz, DMSO-d6) delta-ppm 7.46-7.32 (m, 5H), 7.27-7.22 (m, 2H), 7.13 (m,1 H), 7.03 (m,
With caesium carbonate; In N,N-dimethyl-formamide;
Step A Benzyl 3-bromophenyl Ether To a stirred solution of 3-bromophenol (9.50 g, 54.9 mmol) in degassed DMF (150 mL) at 0 C., under argon, was added Cs2CO3 (35.8 g, 109 mmol). The resulting mixture was stirred for 1 hour, then benzyl bromide (10.3 g, 60.2 mmol) was added and stirring was continued for 2 hours at 0 C. The solvent was removed under reduced pressure, and the residue was partitioned between 20% aqueous NaOH (250 mL) and CHCl3 (500 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluding first with two column volumes of hexane, then with hexane-2% EtOAc to yield the desired product as a white solid.
With potassium carbonate; In methanol; water; N,N-dimethyl-formamide;
Step A Synthesis of 3-(phenylmethoxy)phenyl bromide as an intermediate Under a nitrogen atmosphere, a solution of 50.0 grams (0.29 mole) of 3-bromophenol and 120.0 grams (0.87 mole) of potassium carbonate in 400 mL of N,N-dimethylformamide was stirred, and heated to 80 C. To this was added portionwise, 36.1 mL (0.30 mole) of phenylmethyl bromide during a 20 minute period. Upon completion of addition, the reaction mixture was stirred at 80 C. during a one hour period. After this time, the reaction mixture was allowed to cool to ambient temperature, where it was diluted with 600 mL of water. The mixture was extracted with 600 mL of diethyl ether. The extract was then washed with three 50 mL portions of water, and then it was concentrated under reduced pressure to a residual solid. The solid was recrystallized with 250 mL of methanol, yielding 68.3 grams of 3-(phenylmethoxy)phenyl bromide. The NMR spectrum was consistent with the proposed structure.
With potassium carbonate; In hexane; acetone;
Reference Example 1 3-(Benzyloxy)bromobenzene 3-Bromophenol (50 g, 0.289 mol) was dissolved in acetone (500 ml) and after adding thereto in sequence anhydrous potassium carbonate (80 g, 0.580 mmol) and benzyl bromide (59 g, 0.345 mol), the solution was refluxed under heating for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized (the recrystallization operation was performed twice using hexane as a solvent) to obtain the titled compound (45.0 g, 0.171 mol, 59%).
With potassium carbonate; In acetone; at 25℃; for 72h;
3-Bromophenol (19 g) and benzylbromide (15.7 mL) in acetone (200 mL) are treated with potassium carbonate (60.1 g) and the reaction mixture is stirred at RT for 72 hours. The reaction is filtered and the filter cake is washed with acetone. The filtrate is concentrated and purified via chromatography on SiO2 gel (eluent hexanes/EtOAc 96:4) to give 1-benzyloxy- 3-bromobenzene as a white solid. .
NaH (0.381 g, 9.54 mmol) was added portionwise at 0C to a solution of 3-bromophenol (1.78 g, 10.4 mmol) in DMF (43.4 mL). After the addition was complete, the reaction was allowed to warm to rt and stirred for 15 mm. A solution ofbenzylbromide (1.78 g, 10.4 mmol) in 10 mL of DMF was added dropwise, and the reaction was stirred for 2h. The reaction was then quenched with saturated aq. NH4C1 solution and diluted with EtOAc. The organic phase was washed with 10% aq. LiC1 solution and brine, dried over Na2SO4, filtered and concentrated to yield 1-(benzyloxy)- 3-bromobenzene as a yellow solid. The crude product was converted to the correspondingaldehyde 37A by an Ullmann condensation with ethyl-4-pyrazole carboxylate, followed by reduction with DIBAL-H and oxidation with Mn02 using the general procedures described above (367 mg, 1.32 mmol, 12.7% over 4 steps). MS(ESI) m/z 279.0 (M+H)
26 g
With potassium carbonate; In acetone; for 2h;Reflux;
To a mixture of 3-bromophenol (20 g, 0.115 mol) and potassium carbonate (95 g, 0.69 mol, 6 eq) in acetone (500 ml) was added benzyl bromide (15.12 ml, 0.127 mol, 1.1 eq). The reaction mixture was heated at reflux for 2 hours (TLC showed completion of reaction). The reaction mixture was filtered, washed with acetone and the filtrate was evaporated to dryness. The residue was dissolved in water (200 ml) and ethyl acetate (200 ml). The layers were separated. The organic layer was washed with brine (200 ml), dried over sodium sulfate, filtered and evaporated to dryness. The crude was recrystallized from hexane to give the title compound (26 g) 3 as a white solid. MP 61-62 C.
25.1 g
With potassium carbonate; In acetone; at 70℃; for 1.5h;
17.3 g of 3-bromophenol, 17.1 g of benzyl bromide and 100 mL of acetone were added to a 500 mL round bottom flask and stirring was started. To this was added 28 g of potassium carbonate, the mixture was heated to 70 C. and stirred for 90 minutes. The reaction solution was cooled to 20 C., the reaction solution was poured into 500 mL of water, and extracted three times with 100 mL of ethyl acetate. The collected organic phases were dried over sodium sulfate, concentrated using an evaporator, and then purified by silica gel chromatography (developing solution: hexane / ethyl acetate = 30/1)25.1 g of Intermediate 001A was obtained as a white solid.
1-Benzyloxy-3-bromobenzene (10.56 g, 40.13 mmol), 3,5-dimethoxybenzaldehyde (7.34 g, 44.14 mmol), and n-butyl lithium (17.66 ml, 44.14 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10percent EtOAc in hexane gradient to 40percent EtOAc in hexane in about 40 min.) to give (3-Benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as an oil (11.54 g, 82percent): 1H-NMR (CDCl3) 7.43-7.21 (m, 6H, Ar), 7.04-6.85 (m, 3H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.36 (t, J=2 Hz, 1H, Ar), 5.72 (d, J=3 Hz, 1H, CHOH), 5.04 (s, 2H, CH2), 3.76 (s, 6H, 2OCH3), 2.21 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
82%
With n-butyllithium; In tetrahydrofuran; water;
A stirred mixture of 1-benzyloxy-3-bromo-benzene (10.56 g, 40.1 mmol) and dry THF (35 mL) was cooled to -78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (17.7 mL, 44.1 mmol) and stirred for 20 min. Then a mixture of 3,5-dimethoxy-benzaldehyde (7.34 g, 44.1 mmol) in dry THF (30 mL) was added and stirred for 1 hour at -78° C. The mixture was quenched with isopropanol (18.5 mL, 241 mmol) and added water (30 mL). The mixture was extracted with EtOAc (3*80 mL). The combined organic phases were washed with water (2*80 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3-benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol as an oil (11.54 g, 82percent yield): 1H NMR (CDCl3) delta 2.21 (d, J=4 Hz, 1H, OH), 3.76 (s, 6H, 2OCH3), 5.04 (s, 2H, CH2), 5.72 (d, J=4 Hz, 1H, CH), 6.36 (t, J=2 Hz, 1H, Ar), 6.54 (d, J=2 Hz, 2H, Ar), 6.85-7.04 (m, 3H, Ar), 7.21-7.43 (m, 6H, Ar).
.2 eq BuLi in hexane,1.2 eq TMEDA, 8 eq SO2 in Et2O, 3 eq N-chlorosuccinimide, EtjO, -75 °C to 25 °C, then dioxane, aq NH3. 250C1 16 hA solution of l-benzyloxy-3-bromobenzene (28.3 g) in Et2O (375 mL) is cooled to - 70 °C and treated with TMEDA (19.2 mL) and tt-BuLi in hexane (1.6 M, 79 mL). The solution is stirred at -70 °C for 1 h and transferred into a cooled solution (-70 0C) of SO2 (54.4 g) in Et2O (375 mL). The mixture is kept at -700C for 15 minutes, then allowed to warm to RT over 1 h. The solvent is evaporated and the residue is suspended in aqueous sodium phosphate (IM, 750 mL, pH 6). EtOAc (500 mL) is added and the solution is cooled to 00C. JV-Chlorosuccinimide (43.5 g) is slowly added and the pH is readjusted to pH 6 by addition OfNa3PO4. The reaction mixture is stirred vigorously for 1 h. The phases are separated and the aqueous phase is extracted twice with EtOAc. The combined organic phases are washed with H2O and brine, dried and concentrated to give a yellowish oil. The residue is taken up in dioxane (400 mL) and NH3 in H2O (28percent, 200 mL) is added. The reaction mixture is stirred for 12 h and then concentrated to dryness. The residue is chromatographed on SiO2 gel (eluent hexanes/EtOAc 4:1 to 3:7) to give 3-benzyloxy- benzenesulfonamide as a white powder. API-MS: M-I ?= 262.
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 80℃; for 20h;
526 mg (2.0 mmol) of 1-(benzyloxy)-3-bromobenzene, 209 mul (2.4 mmol) of morpholine, 283 mg (2.8 mmol) of sodium t-butoxide, 9 mg (0.005 mmol) of tris(dibenzylidine acetone)dipalladium (O) 19 mg (0.015 mmol) of (No.)-BINAP were placed in a flask, 5 ml of toluene was added thereto, and the mixture was stirred at 80°C for 20 hours. The reaction mixture was cooled to room temperature, 20 ml of ethyl acetate was added thereto, and filtered through Cellite. The resulting filtrate was concentrated under a reduced pressure, and the residue was subjected to column chromatography using 30percent ethyl acetate/hexane as an eluent to obtain 430 mg (yield 80percent) of 4- (3-(benzyloxy)phenyl)morpholine.
With barium dihydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; under 10343.2 Torr; for 0.116667h;Microwave;
A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.176 g, 0.67 mmol), 3- <n="55"/>methoxycarbonylphenylboronic acid (0.18 g, 1 mmol), barium hydroxide (0.25 g, 1.47 mmol), Pd(PPh3)4 (0.077 g, 0.067 mmol), DME (5 mL) and H2O (3 mL) was microwaved with vigorous stirring using a CEM-discover system (ram time: 2min, hold time: 5min, temperature: 12O0C, pressure: 200 psi, power: 250 W). The crude reaction mixture filtered through a plug of celite and concentrated in vacuo. The residue obtained was purified by flash column chromatography (25percent diethyl ether-hexane) to give the title compound (29) (0.118 g, 60percent yield) as a viscous liquid.1H NMR (500 MHz3 CDCl3) delta 8.27 (t, J = 1.5 Hz, IH), 8.20 (dd, J = 8.0 Hz, J = 1.5 Hz, IH)5 7.76 (dd, J = 8.0 Hz, J = 2.0 Hz, IH)5 7.50 (t, J = 8.0 Hz5 IH), 7.47 (d, J = 7.5 Hz, 2H), 7.42- 7.32 (m, 4H), 7.25-7.22 (m, 2H), 7.00 (dd, J = 8.2 Hz, J = 2.0 Hz, IH), 5.13 (s, 2H), 3.95 (s, 3H).
60%
With barium dihydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 120℃; under 10343.2 Torr; for 0.116667h;Microwave irradiation;
A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.176 g, 0.67 mmol), 3- methoxycarbonylphenylboronic acid (0.18 g, 1 mmol), barium hydroxide (0.25 g, 1.47 mmol), Pd(PPh3)4 (0.077 g, 0.067 mmol), DME (5 mL) and H2O (3 mL) was microwaved with vigorous stirring using a CEM-discover system (ram time: 2min, hold time: 5min, temperature: 120°C, pressure: 200 psi, power: 250 W). The crude reaction mixture filtered through a plug of celite and concentrated in vacuo. The residue obtained was purified by flash column chromatography (25percent diethyl ether-hexane) to give the title compound (29) (0.118 g, 60percent yield) as a viscous liquid.[0280] 29 was confirmed as follows: 1H NMR (500 MHz, CDCl3) delta 8.27 (t, J = 1.5 Hz, 1H), 8.20 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H), 7.76 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 7.50 (t, J = <n="95"/>8.0 Hz, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.42-7.32 (m, 4H), 7.25-7.22 (m, 2H), 7.00 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H), 5.13 (s, 2H), 3.95 (s, 3H).
60%
With barium dihydroxide;Pd(PPh3)4; In 1,2-dimethoxyethane; water;
3'-Benzyloxy-biphenyl-3-carboxylic acid methyl ester (29) A degassed mixture of 3-benzyloxy-phenyl bromide (28) (0.176 g, 0.67 mmol), 3-methoxycarbonylphenylboronic acid (0.18 g, 1 mmol), barium hydroxide (0.25 g, 1.47 mmol), Pd(PPh3)4 (0.077 g, 0.067 mmol), DME (5 mL) and H2O (3 mL) was microwaved with vigorous stirring using a CEM-discover system (ram time: 2 min, hold time: 5 min, temperature: 120° C., pressure: 200 psi, power: 250 W). The crude reaction mixture filtered through a plug of celite and concentrated in vacuo. The residue obtained was purified by flash column chromatography (25percent diethyl ether-hexane) to give the title compound (29) (0.118 g, 60percent yield) as a viscous liquid. 1H NMR (500 MHz, CDCl3) delta 8.27 (t, J=1.5 Hz, 1H), 8.20 (dd, J=8.0 Hz, J=1.5 Hz, 1H), 7.76 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.47 (d, J=7.5 Hz, 2H), 7.42-7.32 (m, 4H), 7.25-7.22 (m, 2H), 7.00 (dd, J=8.2 Hz, J=2.0 Hz, 1H), 5.13 (s, 2H), 3.95 (s, 3H).
1-(3,4,5,6-Tetramethoxy-2-methylphenyl)-1-(3-benzyloxyphenyl)-methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With magnesium; In tetrahydrofuran; at 0℃; for 2h;
REFERENCE EXAMPLE 4 1-(3,4,5,6-Tetramethoxy-2-methylphenyl)-1-3-benzyloxyyhenyl]methanol Under ice-cooling, into a Grignard reagent (150 ml, a tetrahydrofuran solution) prepared from 3-(benzyloxy)bromobenzene (18.4 g, 0.070 mol) and magnesium (1.87 g, 0.077 mol) was dropped a solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (14 g, 0.058 mol) in anhydrous tetrahydrofuran (50 ml) and the mixture was stirred for 2 hours more. The reaction solution was poured into a saturated aqueous solution of ammonium chloride followed by extracting with ether. The extract was washed with a saturated saline and dried. The reaction solution was filtered and the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (23.5 g, 0.055 mol, 95percent).
With ammonium chloride; magnesium; In tetrahydrofuran;
Reference Example 4 1-(3,4,5,6-Tetramethoxy-2-methylphenyl)-1-(3- benzyloxyphenyl) methanol An anhydrous tetrahydrofuran (50 ml) solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (14 g, 0.058 mol) was added dropwise under ice cooling to a Grignard reagent (150 ml tetrahydrofuran solution) prepared from 3-(benzyloxy)bromobenzene (18.4 g, 0.070 mol) and magnesium (1.87 g, 0.077 mol), and the resulting solution was stirred for 2 hours. The reaction solution was poured in an aqueous solution of saturated ammonium chloride and extracted with ether. The extract was washed with saturated brine and then dried. The reaction solution was filtered, the filtrate was concentrated and the obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4:1) to obtain the titled compound (23.5 g, 0.055 mol, 95percent).
With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate;copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 120℃; for 18h;Heating;Product distribution / selectivity;
Step B 3- [4- (3-Benzyloxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester A mixture of 3-benzyloxy-1-bromobenzene (14. 53 g, 55. 2 mmol), 3- (4- hydroxy-2-methyl-phenyl) -propionic acid methyl ester (10.72 g, 55.2 mmol), cesium carbonate (21.59 g, 66.3 mmol), and 2,2, 6,6-tetramethyl-3, 5-heptanedione (2.54 g, 13.8 mmol) in l-methyl-2-pyrrolidinone (100 mL) is purged with N2 and then copper (I) chloride (2.73 g, 27.6 mmol) is added. The reaction mixture is heated to 120 °C for 18 hours under N2. The mixture is then diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 19/1 to 9/1 hexanes/ethyl acetate to afford 10.54 g (51percent) of the titled compound. Rf= 0.53 (100percent hexanes). IH NMR (400 MHz, CDC13) ; MS (ES+) mlz mass calcd for C24H2404 376, found 377 (M + 1, 100percent).
b 3-(Benzyloxy)benzeneboronic acid Prepared according to the method described in Example 51b) from 3-(benzyloxy)bromobenzene (2.16 g, Example 93a), n-butyllithium (2.5 M in hexanes, 3.6 ml) and triisopropyl borate (3.4 g), in tetrahydrofuran (2*10 ml). After work up the residue was purified by column chromatography over silica eluding with ethyl acetate:hexane:acetic acid (20:79.5:0.5) then methanol to give the sub-title compound as a white solid (1.04 g). This was used without analysis.
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; ethyl acetate;
Preparation 3 3-Benzyloxyphenyl Boronic Acid A solution of 3-benzyloxy-bromobenzene 10 g (38 mmol) in 150 mL of anhydrous THF was cooled to -70° C. under a nitrogen atmosphere. 28.5 mL of n-butyl lithium (1.6M in hexanes) was added dropwise to the solution. The reaction mixture was stirred for 30 minutes, then tri-isopropyl borate 10.6 mL (45.6 mmol) was added. The reaction mixture was allowed to warm to ambient temperature over a two hour period. The reaction was quenched by the addition of 200 mL of 1N HCl and the reaction mixture was stirred for an additional hour. The slurry was extracted twice with EtOAc and the organic layer separated and combined. The EtOAc solution was washed twice with brine, dried with Na2 SO4, and evaporated to a yellow oil. The product was crystallized from ether-hexane. This yielded 4.85 g of the title compound as white solid. PMR: Consistent with the proposed structure.
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; ethyl acetate;
Preparation 3 3-Benzyloxyphenyl boronic acid A solution of 3-benzyloxy-bromobenzene 10 g (38 mmol) in 150 mL of anhydrous THF was cooled to -70°C under a nitrogen atmosphere. 28.5 mL of n-butyl lithium (1.6 M in hexanes) was added dropwise to the solution. The reaction mixture was stirred for 30 minutes, then tri-isopropyl borate 10.6 mL (45.6 mmol) was added. The reaction mixture was allowed to warm to ambient temperature over a two hour period. The reaction was quenched by the addition of 200 mL of 1 N HCl andthe reaction mixture was stirred for an additional hour. The slurry was extracted twice with EtOAc and the organic layer separated and combined. The EtOAc solution was washed twice with brine, dried with Na2SO4, and evaporated to a yellow oil. The product was crystallized from ether-hexane. This yielded 4.85 g of the title compound as white solid. PMR: Consistent with the proposed structure.
A mixture of 1-benzyloxy-2-bromobenzene (12.8 g, 48.7 mmol) and n-butyllithium (55 mmol) in THF (150 mL) was stirred for 20 min at -78 °C, treated with tri-iso-propyl borate (34 mL, 147 mmol), stirred for 20 minutes at -78 °C, then 30 minutes at ambient temperature. The mixture was reduced in volume by rotary evaporation, diluted with ethyl acetate washed sequentially with 1M HCl (twice), water, and brine, dried (MgSO4) and concentrated to provide a white solid which was triturated with hexanes to provide the title compound as a white powder (7.04 g). MS (DCI/NH3) m/e 246 (M+NH4)+.
With hydrogenchloride; iodine; magnesium; In tetrahydrofuran; water;
62 g (0.236 mol) of <strong>[53087-13-1]3-benzyloxybromobenzene</strong>, 6.64 g (0.277 mol) of magnesium and 0.3 g of iodine are reacted in 800 ml of tetrahydrofuran at 60° C. for 2 hours to give the solution of the corresponding Grignard compound, which is subsequently added dropwise to a solution, cooled to 0° C. of 28.77 g (0.277 mol) of trimethyl borate in 300 ml of tetrahydrofuran. The mixture is stirred at 0° C. for 1 hour, 74 ml of 37percent strength hydrochloric acid in 300 ml of water are added, and the reaction mixture is subsequently partitioned between water and ether. The organic phase is washed twice with water, dried over sodium sulfate, evaporated and recrystallized from hexane, giving 33.65 g of 3-benzyloxybenzeneboronic acid. STR13
2) 1-benzyloxy-3-bromobenzene (2) undergoes Gridnard reaction to prepare 3-benzyloxyphenyl magnesium bromide, 3-benzyloxyphenyl magnesium bromide undergoes esterification, hydrolysis reaction to prepare the compound 3-benzyloxybenzeneboronic acid (3) In a 250mL two-necked flask add a clean magnesium ribbon 2.18g (90mmol), three grain-doses of iodine. Under nitrogen protection, add 1-benzyloxy-3-bromobenzene (2) 15.79g (60mmol) in dry tetrahydrofuran 40mL, the reaction was heated at reflux for 5 hours to obtain a Grignard reagent 3-benzyloxyphenyl magnesium bromide. The above-described dry tetrahydrofuran was cooled to room temperature, at minus 20 degrees Celsius was added dropwise trimethyl borate 9.36g (90mmol) in dry tetrahydrofuran solution. After addition, 3 hours reaction at room temperature. Then, 100mL saturated aqueous ammonium chloride was added and then hydrolysis reaction overnight. After reaction was complete, recover tetrahydrofuran under reduced pressure, and then acetic acid was added 100mL extraction with ethyl acetate, the organic phasewas washed with water and saturated sodium chloride solution and finally organic phase was dried over anhydrous sodium sulfate and the solvent evaporatedunder reduced pressure to give a white 3-benzyloxybenzene boronic acid (3)7.53g of crude product, yield 55percent.
In a 250 ml two-necked flask2.18 g (90 mmol) of a clean magnesium bar was added,Three iodine, nitrogen protection,15.79 g (60 mmol) of 1-benzyloxy-3-bromobenzene (2)In anhydrous tetrahydrofuran (40 ml)The reaction was heated at reflux for 5 hours,To give Grignard reagent 3-benzyloxyphenyl magnesium bromide.The system was cooled to room temperature,Drop in minus 20 degrees(90 mmol) of a solution of trimethyl borate in anhydrous tetrahydrofuran,After the addition, reaction was carried out at room temperature for 3 hours,Then 100 ml of saturated aqueous ammonium chloride solution was added to the reaction overnight,After completion of the reaction,The tetrahydrofuran was recovered under reduced pressure,Followed by extraction with 100 ml of ethyl acetate,Organic phase followed by water,Saturated sodium chloride solution,The organic phase was finally dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give 3-benzyloxybenzeneboronic acid as white crystals (3)Crude 7.53 g,Yield 55percent.
(2RS,3SR)-3-[3-(1-ethyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-3-methoxy-2-methylpyrrolidine[ No CAS ]
[ 73193-55-2 ]
(2RS,3SR)-3-(3-benzyloxyphenyl)-1-ethoxycarbonyl-3-methoxy-2-methylpyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
The (2RS,3SR)-3-[3-(1-ethyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-3-methoxy-2-methylpyrrolidine used as a starting material was obtained as follows: Using an analogous procedure to that described in the portion of Example 1 which is concerned with the preparation of starting materials, 3-benzyloxybromobenzene was reacted with <strong>[73193-55-2]1-ethoxycarbonyl-2-methylpyrrolidin-3-one</strong> (J. Med. Pharm. Chem., 1962, 5, 755) and the resultant product was reacted with methyl iodide to give (2RS,3SR)-3-(3-benzyloxyphenyl)-1-ethoxycarbonyl-3-methoxy-2-methylpyrrolidine in 65% yield as an oil.
(2S,4R)-4-(3-benzyloxyphenyl)-4-methoxy-2-methyltetrahydropyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With magnesium; In tetrahydrofuran; N-methyl-acetamide; mineral oil;
The (2S,4R)-4-(3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran, used as a starting material, was obtained as follows: A Grignard reagent was prepared by heating a mixture of <strong>[53087-13-1]3-benzyloxybromobenzene</strong> (4.2 g), magnesium (0.4 g), and tetrahydrofuran (10 ml) to reflux for 30 minutes. The mixture was allowed to cool to approximately 40° C. and a solution of (2S)-2-methyltetrahydropyran-4-one (1.55 g) in tetrahydrofuran (7 ml) was added dropwise. The mixture was stirred and warmed to 40° C. for 3 hours. The mixture was partitioned between ethyl acetate and cold dilute aqueous hydrochloric acid solution. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 10:3 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained, as a mixture of diastereoisomers, (2S,4R)- and (2S,4S)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (3.71 g, 92percent), as an oil, which was partly separated to give a fraction (2.33 g) which was enriched in the less polar diastereoisomer. Sodium hydride (55percent w/w dispersion in mineral oil, 0.39 g) was added to a solution of the enriched fraction so obtained (2.33 g) in dimethylformamide (16 ml) which had been cooled to -5° C. and the mixture was stirred at this temperature for 1 hour. Methyl iodide (0.61 ml) was added and the mixture was stirred for 2 hours and allowed to warm to ambient temperature. The mixture was partitioned between ethyl acetate and ice-cold water. The organic phase was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:1 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-(3-benzyloxyphenyl)-4-methoxy-2-methyltetrahydropyran (1.99 g, 82percent), as an oil. NMR Spectrum: (CDCl3, delta values) 1.2(d, 3H), 1.5-1.65(m, 1H), 1.9-2.05(m, 3H), 2.96(s, 3H), 3.8-4.0(m, 3H), 5.1(s, 2H), 6.85-7.05(m, 3H), 7.2-7.5(m, 6H).
benzyloxymethyl 3-(naphth-2-ylmethoxy)phenyl ketone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With hydrogenchloride; In tetrahydrofuran;
The 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]propane-1,3-diol used as a starting material was obtained as follows: A Grignard reagent was prepared by heating a mixture of 3-benzyloxyphenyl bromide (2.55 g), magnesium powder (0.232 g) and tetrahydrofuran (20 ml) to 60° C. for 1 hour. A solution of benzyloxyacetonitrile (1.36 g) in tetrahydrofuran (1 ml) was added dropwise and the mixture was heated to 60° C. for 60 minutes. The mixture was acidified by the addition of 1N hydrochloric acid solution (50 ml) and extracted with diethyl ether. The organic layer was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using methylene chloride as eluent. There was thus obtained benzyloxymethyl 3-(naphth-2-ylmethoxy)phenyl ketone (2.11 g, 65percent) as an oil.
2-(3-hydroxyphenyl)-2,3-dimethoxypropan-1-ol[ No CAS ]
[ 36281-96-6 ]
3-benzyloxyphenyl methoxymethyl ketone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With hydrogenchloride; In tetrahydrofuran;
The 2-(3-hydroxyphenyl)-2,3-dimethoxypropan-1-ol, used as a starting material, was obtained as follows: Methoxyaceonitrile (14 g) in tetrahydrofuran (10 ml) was added to a solution of 3-benzyloxyphenylmagnesium bromide [prepared by heating a mixture of <strong>[53087-13-1]3-benzyloxybromobenzene</strong> (52.6 g), magnesium powder (4.8 g) and tetrahydrofuran (250 ml) to 60° C. for 3 hours] in tetrahydrofuran and the mixture was heated to 60° C. for 30 minutes. The mixture was cooled to ambient temperature and acidified by the addition of 3N hydrochloric acid solution (250 ml). The mixture was extracted with diethyl ether. The organic phase was washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 19:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 3-benzyloxyphenyl methoxymethyl ketone (32.3 g, 63percent), as an orange oil.
(2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With hydrogenchloride
NOTES
Using the procedure described in the portion of Example 1 which is concerned with the preparation of starting materials, a Grignard reagent was prepared from 3-benzyloxybromobenzene (10.5 g) and 2-methyltetrahydropyran-4-one (2.28 g) was added. The mixture was stirred at ambient temperature for 3 hours, acidified by the addition of 2N hydrochloric acid solution and extracted with ethyl acetate. Column chromatography, using a 10:3 v/v mixture of toluene and ethyl acetate as eluent, gave a less polar isomer, (2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (2.45 g, 41%), as an oil, NMR Spectrum (CDCl3, delta values) 1.2(d, 3H), 1.6-1.8(m, 4H),2.0-2.2(m, 1H), 3.9-4.1(m, 3H), 5.1(s, 2H), 6.85-7.45(m, 9H); and a more polar isomer, (2SR,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (1.38 g, 23%), as an oil, NMR Spectrum (CDCl3, delta values) 1.2(d, 3H), 1.6-2.05(m, 4H), 2.3-2.45(m, 1H), 3.3-3.5(m, 2H), 3.9-4.0(m, 1H), 5.1(s, 2H), 6.9-7.5(m, 9H).
(2RS,5SR)-2-dimethylaminomethyl-5-trifluoromethyl-cyclohexanone[ No CAS ]
[ 25818-74-0 ]
[ 585-36-4 ]
(1RS,2RS,5SR)-1-(3-benzyloxy-phenyl)-2-dimethylaminomethyl-5-trifluoromethyl-cyclohexanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With ammonium chloride; magnesium; In tetrahydrofuran; acetonitrile;
1st Step (1RS,2RS,5SR)-1-(3-benzyloxy-phenyl)-2-dimethylaminomethyl-5-trifluoromethyl-cyclohexanol (26) 43.9 g (167 mmole) 3-benzyloxy-1-bromobenzene, dissolved in 200 ml of dry tetrahydrofuran, were added drop-wise to 4.06 g (167 mmole) magnesium turnings in 40 ml of dry tetrahydrofuran so that the reaction mixture boiled gently. After the addition of 3-benzyloxy-1-bromobenzene was complete, the mixture was heated for one hour under reflux and was thereafter cooled to 5-10 C. 30.8 g (139 mmole) (2RS,5SR)-2-dimethylaminomethyl-5-trifluoromethyl-cyclohexanone, prepared from <strong>[585-36-4]3-trifluoromethyl-cyclohexanone</strong> and dimethylaminomethylene chloride in acetonitrile, dissolved in 80 ml of dry tetrahydrofuran, were added at this temperature. The reaction mixture was allowed to stand overnight and was then cooled to 5-10 C. again. The Grignard solution was decomposed by the addition of 150 ml of 20% ammonium chloride solution. The reaction mixture was diluted with 200 ml of ether, the organic phase was separated off and the aqueous phase was extracted twice with 100 ml ether. The combined organic phases were dried over sodium sulphate. After removing the solvent by distillation, the residue (60.6 g) was introduced on to an 8*50 cm column packed with silica gel and extracted with ethyl acetate/methanol. 27.8 g (50% theoretical) of base (26) were obtained.
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃;
Benzylation of 3-bromophenol 1 with benzyl chloride and potassium carbonate in DMF affords compound 2. Palladium (0)-catalyzed cross-coupling reaction of 2 with bis(pinacolato)diboron, PdCl2(dppf), and potassium carbonate in DMSO at 80° C. gives rise to compound 3 (Ishiyama, T; Murata, M; Miyaura, N. J. Org. Chem. 1995, 60, 7508). Debenzylation of 3 with Pd/C at 60 psi hydrogen in MeOH produces the target compound 4 (Pennington, T. E.; Kardiman, C; Hutton, C. A. Tetrahedron Lett. 2004, 45, 6657).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 1h;Microwave irradiation;
A solution of 1-(benzyloxy)-3-bromobenzene (for a preparation see Intermediate 21 , 263 mg, 1.0 mmol) in 1 ,4-dioxane (8 mL) was added to a mixture of £>/s(pinacolato)diboron (1 .27 g, 5.0 mmol), potassium acetate (392 mg, 4.0 mmol) and [1 ,1 - t)/'s(diphenylphosphino)ferrocene]dichloropalladium(ll), (PdCI2(dppf)) (37 mg, 5 molpercent). The reaction mixture was heated in a microwave at 1 10°C for 60 minutes. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite. The filtrate was dried and evaporated to give 2-(3-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (310 mg, 1.000 mmol, 100 in the next step without further
N-methoxy-N-methyl-4-morpholinobutanamide[ No CAS ]
[ 850664-04-9 ]
Yield
Reaction Conditions
Operation in experiment
35%
Step3. 4-(4-morpholinyl)-1-{3-[(phenylmethyl) oxy] phenyl}-1-butanone Under argon, to a solution of 1-bromo-3-[(phenylmethyl) oxy] benzene (2.04 g, 7.76 mmol) in THF (30 mL) at-78 °C, was added dropwise n-BuLi (5.1 mL, 1.6 M in Hexanes), 20 min after the addition, this solution was added to a solution the product from Step 3 (1.68 g, 7.76 mmol) in THF (30 mL) under argon at-78 °C. 15 min later, the reaction mixture was slowly warmed to 0 °C. The reaction mixture was poured into a mixture of EtOAC and NH4C1, then extracted with EtOAC (2X), organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was then purified with flash chromatography (hexanes/ethyl acetate 1: 4), to afford the title compound as a colorless oil (932 mg, 35percent).
With hydrogenchloride; N-Bromosuccinimide; In water; acetone; at 20℃; for 0.5h;
a) Preparation of racemic 6-(benzyloxy)-1,4-dihydro-1,4-epoxynaphthalene 54 Aq. 1 M HCl (0.16 mL) was added to a solution of 3-(benzyloxy)-1-bromobenzene (commercially available from Aldrich, 4.24 g, 16.1 mmol) and NBS (2.87 g, 16.1 mmol) in acetone (16 mL) at RT. After stirring for 30 min the solvent was removed under vacuum. Hexane (20 mL) was added and the resulting white solid filtered off (succinamide). The solvent was removed under vacuum to give 4-(benzyloxy)-1,2-dibromobenzene (5.5 g). The dibromide was used in the next step without further purification. nBuLi (1.6 M in hexanes; 10.0 mL, 16.1 mmol) was added dropwise to a solution of furan (5.8 mL, 80 mmol) and 4- (benzyloxy)-1,2-dibromobenzene (5.5 g) in THF (80 mL) at -78 °C. After 30 min, the reaction was quenched with water (100 mL). After warming to RT the layers were separated and the aqueous layer was extracted with Et2O (3 x 100 mL). The combined organic layers were dried (MgSO4), and the solvent evaporated under vacuum. The residue was purified by column chromatography (silica, 100percent hexane --> 20percent EtOAc in hexane) to give 6-(benzyloxy)-1,4-dihydro-1,4-epoxynaphthalene 54 (2.01 g, 50percent, over 2 steps) as a colourless oil, which solidified on standing; Rf 0.35 (25percent EtOAc in hexane); mp = 75-77 °C; IR (neat)/cm-1 3091w, 1599m, 1455s, 1283m, 1222s, 1086m; 1H NMR (400 MHz) delta 7.41-7.28 (m, 5H), 7.10 (d, J= 8, 1 H), 7.01 (dd, J = 5.5, 1.5, 1 H), 6.98-6.96 (m, 2H), 6.48 (dd, J = 8, 2.5, 1 H), 5.65 (dd, J = 8, 1.5, 2H), 5.00 (s, 2H); 13C NMR (100 MHz) delta 156.6, 151.0, 143.4, 142.2, 140.7, 137.0, 128.5, 127.9, 127.4, 120.3, 110.3, 108.4, 82.4, 82.0, 70.4; MS m/z (EI+) 250 (M+, 15), 91 (100); HRMS calcd for C17H14O2 (M+) 250.0994, found 250.0999.
Iodine, warmed up with magnesium, was added to a suspension of magnesium tunings (i .29 g,52.8 mmol) in dry THF (50 mL). The mixture was ref luxed and about 5percent of a solution of 3-bromophenol (i3.9 g, 52.8 mmol) was added. When the reaction had started, the solution of the bromide was added drop-wise and the mixture was then ref luxed for one more hour. Themixture was cooled down to about 5 00 and a solution of the cyclopentanone (4.44 g, 52.8 mmol) in THF (50 mL) was added drop-wise. The mixture was stirred at rt for 72 h, then the reactio was quenched with cooled saturated ammonium chloride solution and extracted with diethyl ether (x3). The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The product was purified by silica gel chromatography (isohexane / EtOAc),which gave the title compound (8.5 g, 54percent).
54%
With iodine; magnesium; In tetrahydrofuran; at 5 - 20℃; for 72h;Reflux;
Iodine, warmed up with magnesium, was added to a suspension of magnesium tunings (1.29 g, 52.8 mmcl) in dry THF (50 mL). The mixture was refluxed and about 5percent of a solution of 3- bromophenol (13.9 g, 52.8 mmcl) was added. When the reaction had started, the solution of thebromide was added drop-wise and the mixture was then refluxed for one more hour. The mixture was cooled down to about 5 °C and a solution of the cyclopentanone (4.44 g, 52.8 mmcl) in THF (50 mL) was added drop-wise. The mixture was stirred at rt for 72 h, then the reactio was quenched with cooled saturated ammonium chloride solution and extracted with diethyl ether (x3). The organic phase was washed with brine, dried (Na2SO4), filtered andconcentrated. The product was purified by silica gel chromatography (isohexane / EtOAc), which gave the title compound (8.5 g, 54percent).
54%
Iodine, warmed up with magnesium, was added to a suspension of magnesium tunings (1 .29 g, 52.8 mmol) in dry THF (50 ml_). The mixture was refluxed and about 5percent of a solution of 3- bromophenol (13.9 g, 52.8 mmol) was added. When the reaction had started, the solution of the bromide was added drop-wise and the mixture was then refluxed for one more hour. The mixture was cooled down to about 5 °C and a solution of the cyclopentanone (4.44 g, 52.8 mmol) in THF (50 mL) was added drop-wise. The mixture was stirred at rt for 72 h, then the reactio was quenched with cooled saturated ammonium chloride solution and extracted with diethyl ether (x3). The organic phase was washed with brine, dried (Na2S04), filtered and concentrated. The product was purified by silica gel chromatography (isohexane / EtOAc), which gave the title compound (8.5 g, 54percent).
1.85 g of magnesium was suspended in 15 ML of diethyl ether, to which a catalytic amount of iodine was added and then a solution of 20.00 g of 1-(benzyloxy)-3-bromobenzene in 40 ML of diethyl ether was added dropwise and this mixture was stirred for 8 hours while heating it under reflux.. The reaction mixture was cooled to 5°C, to which a solution of 6.72 ML of cyclopentanone in 20 ML of diethyl ether was added dropwise, and this mixture was stirred for one hour at room temperature.. Then an aqueous solution of ammonia chloride was added to the ice-cooled reaction mixture, and the organic phase was separated therefrom.. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure.. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 7.65 g of 1-[3-(benzyloxy)phenyl] cyclopentanol as yellow oil. NMR(400MHz,CDCl3) delta value: 1.52(1H,s), 1.79-1.88(2H,m), 1.93-2.04(6H,m), 5.08(2H,s), 6.85(1H,ddd,J=8.4,2.8,1.2Hz), 7.08(1H,ddd,J=7.6,1.6,0.8Hz), 7.16-7.17(1H,m), 7.24-7.46(6H,m)
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,2-dimethoxyethane; at 20 - 110℃;
To a solution of 1-(benzyloxy)-3-bromobenzene (1.00 g) in 1,2-dimethoxyethane (15 mL) were added tris(dibenzylideneacetone)dipalladium(0) (180 mg), 2'-[dicyclohexylphosphino]-N,N-dimethylbiphenyl-2-amine (150 mg), piperidine (500 muL), and tripotassium phosphate (2.5 g) at room temperature, and the mixture was stirred at 110°C for 21 hours. After the reaction mixture was cooled to room temperature, insolubles were separated by filtration and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0 - 85/15) to obtain 1-[3-(benzyloxy)phenyl]piperidine (722 mg).
A 1 liter round bottom flask containing degassed toluene (400 mL) is charged with benzophenone hydrazone (32.86 g, 0.167 mol), palladium acetate (Pd(OAc)2, 0.34 g, 0.0015 mol) and BINAP ((2,2'-bis(diphenylphosphino)-1,1'-binapthyl, 1.42 g, 0.0023 mol) (notes 1, 2).The mixture is heated to 80 0C for 15 minutes for activation of the catalyst (note 3). The heating is removed and the mixture is allowed to cool to 60 to 70 °C. 3-benzyloxy EPO <DP n="23"/>bromobenzene (40.07 g, 0.152 mol) and sodium tert-butoxide (20.42 g, 0.212 mol) are added (notes 4, 5) and the mixture is heated to 100 0C with stirring for 2 hours (note 6). An aliquot is removed and analyzed by HPLC (notes 7, 8). Upon completion of the reaction, the mixture is allowed to cool below 45 0C and is washed twice with water (1st wash 400 ml, 2nd wash 200 ml) (note 9). The organic layer is filtered through Celite.(R). (note 10) and the cake is washed with toluene (1 x 120 ml). The product-rich filtrate is distilled at atmospheric pressure to a total volume of 321 ml. After cooling below 70 0C, isopropanol (265 ml_) is added and heating is resumed to displace toluene until a total volume of 321 ml is reached. This sequence is repeated 3 times for effective removal of the toluene (note 11). The solution is cooled below 70 0C, and a sample is removed and analyzed by 1H NMR (note 12). Upon acceptable toluene removal, the reaction is cooled below 60 0C. Diisopropyl ether (265 ml) is added and heating is resumed to displace the isopropanol until a total volume of 321 ml is reached (note 13). This sequence is repeated 2 times for effective removal of the isopropanol. A sample is removed and analyzed by 1H NMR (note 14). Upon acceptable removal of the isopropanol, the solution is allowed to cool to room temperature, at which point the solution becomes a slurry (note 15). After granulating for 40 minutes at ambient temperature, the slurry is cooled and granulated an additional 30 minutes at -10 °C. The tan solids are filtered at -10 °C and dried for 18 hours in a vacuum oven at 50 0C to provide 47.85 g (83percent) of the title product as a solid (notes 16 and 17). 1H NMR of sample: (300 MHz, CDCI3) 5.10 (s, 2H), 6.3-6.5 (dd, 1 H), 6.75-6.85 (s,1 H), 7.0-7.1 (t, 1H), 7.2-7.7 (m, 16H), 10.12 (NH). Notes;1. The flask is equipped with an overhead stirrer, internal temperature probe, and a condenser with nitrogen inlet. 2. Degassing is accomplished via nitrogen flow through a gas dispersion tube immersed in the toluene for 30 minutes.3. The catalyst is activated when the color changes from a red-orange slurry to a deep purple-red or brown-red slurry; either color change indicates the activation of the catalyst. 4. Sodium tert-butoxide should be added quickly to minimize exposure to moisture.5. If the sodium tert-butoxide is added above 70 0C, color changes from a deep purple-red to a dark brown.6. The initial dark red solution became a red-brown slurry. 7. The reaction is monitored for completion using HPLC. HPLC conditions: Kromasil C4 column, 5 mum, 4.6 x 150 mm, 40 °C column chamber, flow rate = 1.0 mL/min, 210 nm, lsocratic 70/30 acetonitrile/aqueous (1.0 mL 70percent HCIO4 in 1 L H2O). Method ends at 15 EPO <DP n="24"/>minutes. Retention times: N-(3-benzyloxyphenyl) benzophenone hydrazone = 8.7 min, 3- benzyloxy bromobenzene = 4.9 min, toluene = 3.3 min, benzophenone hydrazone = 2.5 min.8. The reaction is deemed complete when less than 3percent 3-benzyloxy bromobenzene remains as determined by HPLC. 9. Most solids will be dissolved in the first aqueous layer. Trace remaining insoluble material at the interface is taken with the aqueous layer during separations10. This filtration is to remove residual insoluble material.11. Solids typically precipitate during these additions, but return to solution upon heating. 12. There should be less than 7percent toluene remaining in the solution as determined by NMR, before proceeding.13. Solids typically precipitate during these additions, but return to solution upon heating.14. There should be less than 25percent of isopropanol remaining in the reaction (determined by NMR) prior to final cooling for product isolation.15. Occasionally, solids failed to precipitate at room temperature. Seeding the solution resulted in slurry formation.16. The reactor may be rinsed out with the mother liquor and this washed over cake to recover additional solids if deemed necessary. Rinsing with clean solvent is not recommended due to the high solubility of the product.17. The purity by HPLC is 93percent (210 nm) and 97percent (254 nm).
Magnesium (172.4 mg; made by Wako Pure Chemical Industries Co., Ltd.), dehydrated THF (5 mL), dibromoethane (20 muL; made by Tokyo Chemical Industry Co., Ltd.), and 1-(benzyloxy)-3-bromobenzene-THF solution [15 mL; solution prepared by dissolving 1-(benzyloxy)-3-bromobenzene (1.3146 g; made by Tokyo Chemical Industry Co., Ltd.) in dehydrated THF (15 mL)] were added and stirred for one hour by reflux in a nitrogen atmosphere.The reaction solution was cooled to - 78°C and bubbled for 20 minutes by SO2 gas.The reaction solution was brought to room temperature, bubbled for 10 minutes with nitrogen gas, and filtered.The filtrate was concentrated, and the residue obtained was dissolved in CH2Cl2 (25 mL), then cooled to 0°C. SO2Cl2 (0.6 mL; made by Wako Pure Chemical Industries Co., Ltd.) was added to this solution and stirred overnight while warming to room temperature.Water was added to the reaction solution.After filtering by Celite, the filtrate was washed with brine.The organic layer was dried by anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.The title compound was obtained as a crude product (1.3811 g).This crude product was used in the next reaction without any particular purification.
Step 1 : Preparation of tert- utyl 4-(3-Benzyloxyphenyl)-4-hydroxypiperidine-l- carboxylate. A suspension of magnesium metal (0.144g, 6.0 mmol) in THF (10 mL) was rapidly stirred for 30 minutes under nitrogen then a solution of <strong>[53087-13-1]3-benzyloxybromobenzene</strong> (1.58g, 6.00 mmol) in THF (10 mL) added slowly via dropping funnel. Once approximately 1 mL of the bromide solution had been added a crystal of iodine was added to the reaction and the mixture gently heated until Grignard formation began. The remaining bromide solution was then added at a rate to maintain a reaction temperature range of 50-60 °C. Once addition was complete the reaction was heated to gentle reflux for 1 hour then cooled in an ice bath. A solution of tert- utyl 4-oxopiperidine-l-carboxylate (l .OOg, 5.02 mmol) in THF (10 mL) was the added to the reaction over a period of 30 minutes then the mixture was allowed to warm to room temperature with stirring over a 2 hour period. After this time the reaction was quenched by the addition of 25percent ammonium chloride solution (50 mL) and the layers separated. The aqueous was extracted with ethyl acetate (2 x 10 mL) and the combined organics were washed with water (20 mL) and brine (20 mL) then dried over magnesium sulfate. Subsequent filtration, concentration and purification of the residue by column chromatography (Si02, 0-25percent ethyl acetate /heptanes) afforded a 61 percent yield of tert- butyl 4-(3-benzyloxyphenyl)-4-hydroxypiperidine-l-carboxylate as a viscous clear oil that became a white solid on standing.1H NMR (CDC13): delta = 7.41-7.33 (m, 5H), 7.29 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 1.9 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 8.0, 2.1Hz, 1H), 5.09 (s, 2H), 4.03 (m, 2H), 3.25 (bt, J = 12Hz, 2H), 2.00 (bt, J = 11.1Hz, 2H), 1.73 (bd, J= 12.6Hz, 2H) and 1.50 ppm (s, 9H).
General procedure: All glassware used in the following procedure was flame dried and then cooled under nitrogen prior to use. A portion (1 mmol) of the required aryl bromide (10.00 mmol) was added to a suspension of magnesium turnings (250 mg, 10.5 mmol) in tetrahydrofuran (12 mL) containing a few iodine crystals and the mixture gently heated whilst stirring vigorously. Once the reaction forming the Grignard reagent had initiated (reflux became self-sustaining) the remaining bromobenzene was added dropwise at such a rate that gentle reflux was maintained. The mixture was then heated at reflux until the magnesium was consumed (usually 30-60 min) and then was cooled for 30 min using an ice bath. A solution of 1-benzyl 4-piperidone (5.00 - 6.25 mmol) in tetrahydrofuran (8 mL) was added dropwise over 1-2 h and the mixture was stirred for 1 h and then the ice bath was removed and the reaction mixture allowed to warm to room temperature whilst stirring for at least a further 2 h. The reaction was quenched by the addition of saturated ammonium chloride solution (60 mL) and extracted into diethyl ether (2 .x. 30 mL) followed by ethyl acetate (3 .x. 30 mL). The organic phases were combined and subjected to standard work up conditions to give the required crude product. Purification of the title compound was achieved by flash chromatography on silica or, where indicated, by elution through a short length silica column using the eluant specified. In some cases, the crude piperidinol was dehydrated directly without purification as indicated.
With potassium hexamethylsilazane; In 1,4-dioxane; at 100℃; for 22h;
Example 66; 2-[4-[2-[5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-yl]vinyl]-3-cyano-5,5-dimethyl-2(5H)-furanylidene]propanedinitrile(66-1) 4-[(3-benzyloxyphenyl)butylamino]-1-butanol In 75 ml of dioxane were dissolved 5.19 g (19.7 mmol) of <strong>[53087-13-1]3-benzyloxybromobenzene</strong> and 3.72 g (25.6 mmol) of 4-butylamino-1-butanol. To this mixture was added 5.89 g (29.5 mmol) of potassium hexamethyldisilazide and the mixture was stirred with heating at 100° C. for 22 hours. After the reaction mixture was poured into 200 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 2.22 g of a light brown oily matter (yield: 34.4percent). 1H-NMR (600 MHz, CDCl3) delta: 0.93 (3H, t, J=7.7 Hz), 1.29-1.35 (2H, m), 1.51-1.66 (6H, m), 3.22 (2H, t, J=7.7 Hz), 3.26 (2H, t, J=7.7 Hz), 3.66 (2H, t, J=6.9 Hz), 5.05 (2H, s), 6.27-6.31 (3H, m), 7.11 (1H, t, J=8.2 Hz), 7.30-7.33 (1H, m), 7.37-7.39 (2H, m), 7.43-7.45 (2H, m)
With 1-n-butyl-3-methylimidazolim bromide; at 200 - 220℃; for 0.166667h;Microwave irradiation; Inert atmosphere;
General procedure: To a microwave tube was added alkyl aryl ether (1.0 mmol) and 1-n-butyl-3-methylimidazolium bromide (0.65 g, 3.0 mmol). The reaction tube was flushed with argon and then was irradiated at 20 W for the designated time period with air-flow cooling to prevent overheating (power control mode). After cooled to room temperature, the reaction mixture was acidified with 1 NHCl solution and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was washed with water and brine, and dried over anhydrous MgSO4 and the solvent was evaporated under vacuum. Purification of the crude product by column chromatography (ethyl acetate in n-hexane)afforded the desired product.
(3-(benzyloxy)phenyl)dimethyl(3,4,5-trimethoxyphenyl)silane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.1%
To a solution of 5-bromo-1,2,3-trimethoxyphenol (494.1mg, 2mmol) and 1-(benzyloxy)-3-bromobenzene (6b) (526.3mg, 2mmol) in dry tetrahydrofuran (15mL) was added n-butyl lithium in n-hexane (2.65M, 1.51mL, 4mmol) under an Ar atmosphere at ?78°C. This was stirred at the same temperature for 1h, and then dichlorodimethylsilane (0.27mL, 2.2mmol) was added. The mixture was stirred at ?78°C for 2h, and at room temperature for 3h. The reaction was quenched with NH4Cl aq, and the whole was extracted with ethyl acetate. The extract was successively washed with water and brine, and then dried over MgSO4. The solvent was evaporated, and the residue was purified by means of silica gel column chromatography (hexane/ethyl acetate=9/1) to give 10 (327.5mg, 40.1percent) as a colorless oil. 1H NMR (500MHz, CDCl3): delta 7.42?7.29 (6H, m), 7.14?7.11 (2H, m), 7.00?6.97 (1H, m), 6.70 (2H, s), 5.04 (2H, s), 3.86 (3H, s), 3.83 (6H, s), 0.53 (6H, s).13C NMR (500MHz, CDCl3): delta 158.35, 153.10, 140.00, 139.27, 137.08, 133.06, 129.19, 128.68, 128.08, 127.67, 126.74, 120.86, 115.24, 110.96, 70.00, 60.87, 56.26, ?2.14. HRMS(FAB+) m/z: calcd for C24H28O4Si 408.1757, found 408.1762 (M+)
With 2,2,6,6-tetramethylpiperidinyl-lithium; In tetrahydrofuran; hexane; at -78℃;Inert atmosphere;
General procedure: To a 100 mL flamed-dried flask equipped with stir bar and a nitrogen-filled balloon was added THF (20 mL). The system was cooled to 0 °C with an ice-water bath before n-BuLi (2.5 M in hexane, 6 mmol, 1.5 equiv) was added dropwise. Upon completion, the system was warmed to rt and stirred for 16 h under nitrogen atmosphere. At the same time, to a 30 mL flamed-dried flask equipped with a stir bar and a nitrogen-filled balloon were added 2,2,6,6-tetramethylpiperidine (4.8 mmol, 1.2 equiv) and THF (12 mL). After cooling to 0 °C with an ice-water bath, n-BuLi (2.5 M in hexane, 4.8 mmol, 1.2 equiv) was added dropwise and the reaction was stirred at 0 °C for 0.5 h. The previous 100 mL flask was cooled to 78 °C with an acetone-dry ice bath and benzyne precursor (4 mmol, 1.0 equiv) in THF (5 mL) was added before in situ generated lithium tetramethylpiperidine was added dropwise. The reaction was monitored by TLC and was quenched by adding aqueous NH4Cl. The mixture was then warmed to rt and H2O (30 mL) was added. The mixture was extracted with ethyl acetate (30 mLx3), washed with brine, and dried with Na2SO4. The combined organic extract was concentrated under reduced pressure and purified by column chromatography on silica gel to afford the following compounds. 4.4.2 5-(Benzyloxy)bicyclo[4.2.0]octa-1,3,5-trien-7-ol (7c) Compound 7c was obtained as a white solid from 6c in 52percent yield (470 mg) and 6d in 70percent yield (637 mg), Rf=0.2 (Hexane/EtOAc=5:1); 1H NMR (400 MHz, CDCl3) delta 7.46-7.21 (m, 6H), 6.81 (dd, J=8.5, 0.7 Hz, 1H), 6.74 (dd, J=7.2, 0.5 Hz, 1H), 5.32 (dd, J=39.8, 12.2 Hz, 2H), 5.22 (ddd, J=9.6, 4.6, 1.9 Hz, 1H), 3.58 (dd, J=14.5, 4.6 Hz, 1H), 3.00 (ddt, J=14.5, 1.7, 0.8 Hz, 1H), 2.21 (d, J=9.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) delta 153.5 (s), 144.0 (s), 137.4 (s), 131.4 (s), 131.0 (s), 128.5 (s), 127.9 (s), 127.2 (s), 115.9 (s), 114.9 (s), 71.1 (s), 70.8 (s), 42.4 (s). IR: nu 3071, 2956, 2929, 1719, 1600, 1581, 1475, 1390, 1350, 1265, 1155, 1108, 1032, 845 cm-1. HRMS calcd for [M+Na]+: 249.0891, found: 249.0889. Mp (°C): 81-83.
With 2,2,6,6-tetramethylpiperidinyl-lithium; In tetrahydrofuran; hexane; at -78℃;Inert atmosphere;
General procedure: To a 30 mL flamed-dried flask equipped with stir bar and a nitrogen-filled balloon were added 2,2,6,6-tetramethylpiperidine (1.2 equiv) and THF (12 mL). After cooled to 0 C with an ice waterbath, n-BuLi (2.5 M in hexane, 1.2 equiv) was added dropwise and the reaction was stirred at 0 C for 0.5 h. To a 100 mL flame-dried flask equipped with a stir bar and a nitrogen-filled balloon were added THF (30 mL), benzyne precursor (1 equiv), and corresponding ketene silyl acetals9 (1.5 equiv) and was cooled to 78 C with an acetone-dry ice bath before in situ generated lithium tetramethylpiperidine was added dropwise. The reaction was monitored and aqueous NH4Cl was added upon disappearance of the benzyne precursor. After warming to rt, the reaction mixture was extracted with ethyl acetate (30 mLx3), washed with brine, and concentrated under reduced pressure. Acetonitrile (30 mL) was added to the concentrated reaction system and cooled to 0 C with an ice-water bath followed by slow addition of hydrofluoric acid (27.6 M, 10 equiv). Upon completion, the reaction was heated to 40 C overnight before water (100 mL) was added. The mixture was extracted with ethyl acetate (30 mLx3), washed with brine, and dried with Na2SO4. The combined organic extract was concentrated under reduced pressure and purified by column chromatography on silica gel to afford the following compounds. 4.6.1. 5-(Benzyloxy)-8-methylbicyclo[4.2.0]octa-1,3,5-trien-7-one (9). Compound 9 was obtained as light yellow oil (271 mg) from 6d and tert-butyl((1-methoxyprop-1-en-1-yl)oxy)dimethylsilane in 23% yield, Rf=0.6 (Hexane/EtOAc=5:1); 1H NMR (400 MHz, CDCl3) delta 7.48-7.30 (m, 6H), 7.02 (d, J7.0 Hz, 1H), 6.89 (d, J8.4 Hz, 1H), 5.45 (s, 2H), 4.21 (q, J7.2 Hz, 1H), 1.47 (d, J7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) delta 189.3 (s), 157.0 (s), 152.6 (s), 137.8 (s), 136.4 (s), 130.7 (s), 128.5 (s), 128.2 (s), 127.9 (s), 116.7 (s), 114.2 (s), 74.0 (s), 58.3 (s), 15.0 (s). IR: gamma 2964, 2927, 2360, 2342, 1756, 1602, 1571, 1473, 1452, 1386, 1273, 1161, 1125, 991, 886, 795, 767, 748, 699 cm-1. HRMS calcd for C16H14NaO2 [M+Na]+: 261.0886, found: 261.0879.
With 2,2,6,6-tetramethylpiperidinyl-lithium; In tetrahydrofuran; hexane; at -78℃;Inert atmosphere;
General procedure: To a 30 mL flamed-dried flask equipped with stir bar and a nitrogen-filled balloon were added 2,2,6,6-tetramethylpiperidine (1.2 equiv) and THF (12 mL). After cooled to 0 °C with an ice waterbath, n-BuLi (2.5 M in hexane, 1.2 equiv) was added dropwise and the reaction was stirred at 0 °C for 0.5 h. To a 100 mL flame-dried flask equipped with a stir bar and a nitrogen-filled balloon were added THF (30 mL), benzyne precursor (1 equiv), and corresponding ketene silyl acetals9 (1.5 equiv) and was cooled to 78 °C with an acetone-dry ice bath before in situ generated lithium tetramethylpiperidine was added dropwise. The reaction was monitored and aqueous NH4Cl was added upon disappearance of the benzyne precursor. After warming to rt, the reaction mixture was extracted with ethyl acetate (30 mLx3), washed with brine, and concentrated under reduced pressure. Acetonitrile (30 mL) was added to the concentrated reaction system and cooled to 0 °C with an ice-water bath followed by slow addition of hydrofluoric acid (27.6 M, 10 equiv). Upon completion, the reaction was heated to 40 °C overnight before water (100 mL) was added. The mixture was extracted with ethyl acetate (30 mLx3), washed with brine, and dried with Na2SO4. The combined organic extract was concentrated under reduced pressure and purified by column chromatography on silica gel to afford the following compounds. 4.6.2. 8-Ethyl-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (10). Compound 10 was obtained as colorless oil (876 mg) from 6a and tert-butyl((1-methoxybut-1-en-1-yl)oxy)dimethylsilane in 62percent yield, Rf=0.8 (Hexane/EtOAc=5:1); 1H NMR (400 MHz, CDCl3) delta 7.40 (dd, J8.4, 7.1 Hz, 1H), 6.99 (d, J7.1 Hz, 1H), 6.78 (d, J8.4 Hz,1H), 4.13-4.06 (m, 4H), 1.98-1.72 (m, 2H), 1.04 (t, J7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) delta 188.9 (s), 156.0 (s), 153.5 (s), 137.5 (s), 131.1(s), 116.0 (s), 114.6 (s), 65.0 (s), 59.7 (s), 23.3 (s), 11.5 (s). IR: gamma 2963, 2934, 2876, 2359, 2340, 1766, 1602, 1574, 1482, 1455, 1435, 1277, 1157, 1123, 1020, 941, 799 cm-1. HRMS calcd for C16H14NaO2[MNa]: 261.0886, found: 261.0879.
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; DavePhos; In toluene; at 100℃; for 2h;
General procedure: Aryl benzyloxy halide Vc (1 eq.) and amine IVc (1 eq.) were suspended in dry toluene. Then, compounds Pd2(dba)3 (0.02 eq.), DavePhos (0.06 eq.) and t-BuO"K+ (2 eq.) were added. The resulting mixture was stirred 2 hours at 100°C. The reaction mixture was washed with a saturated solution of NH4C1 and the organic phase was collected and dried over sodium sulfate, then filtered. The evaporation under reduced pressure of the organic phase gave crude which was adsorbed on silica gel and purified by column chromatography (Eluent: cyclohexane/ethyl acetate 9: 1). The fractions were collected and evaporated under reduced pressure. The title compound was synthesized according to the general procedure II method C sing commercially available l-benzyloxy-3-bromo-benzene (200.0 mg, 0.76 mmol), 4,4-difluoropiperidine hydrochloride (119.8 mg, 0.76 mmol), Pd2(dba)3 (13.9 mg, 0.02 mmol), DavePhos (17.9 mg, 0.06 mmol) and t-BuO"K+ (170.6 mg, 1.52 mmol) in dry Toluene (5 mL).
To a suspension of m-bromophenol (1) (15.57 g, 90 mmol) in dehydrated alcohol (300 mL) was added anhydrous potassium carbonate (37.32 g, 270 mmol) and benzyl chloride (11.50 mL, 99 mmol). The mixture was refluxed for 4 h. Filtration and evaporation of alcohol was done in a vacuum. The residue was extracted with EtOAc. The combined organic layers were washed with water, NaOH (2 M), brine, and HCl (2 M), dried over Na2SO4, and concentrated to give (2) (22.02 g, 93percent) as a yellow solid. A 250 mL, two-necked, round-bottomed flask containing dry magnesium (2.18 g, 90 mmol) and iodine (trace) was equipped with two rubber septum stirred under the protection of nitrogen. The solution of (2) (15.79 g, 60 mmol) in 40 mL of anhydrous THF was added slowly into the flask through a syringe at a rate to remain reflux. After addition finishing, the resulting mixture was kept in refluxing for 5 h with stirring. The mixture in cooled to -30 °C, then the trimethylborate (9.36 g, 90 mmol) in 60 mL of anhydrous THF was added slowly through a syringe. After addition finishing, the resulting mixture was allowed to stir at room temperature for overnight and then treated with saturated NH4Cl solution, stirred for 1 h at room temperature. Then THF was removed by rotary evaporation. The aqueous layer was extracted with EtOAc and dried over Na2SO4, filtered and concentrated to afford the yellow crude product. The crude product was purified by recrystallization from water affording (3) as a white solid (7.53 g, 55percent).
2-[3-(benzyloxy)phenyl]cyclohexane-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium phosphate; palladium diacetate; di-tert-butyl (2'-methyl-[1,1'-biphenyl]-2-yl)phosphine; In 1,4-dioxane; tert-Amyl alcohol;Inert atmosphere; Reflux;
Example 128A2- [3 -(benzyloxy)phenyl]cyclohexane- 1,3 -dioneA 1 L round-bottomed flask was charged with 1-(benzyloxy)-3-bromobenzene (45.5g, 173 mmol), tert-amyl alcohol (200 mL) and dioxane (400 mL), and the contents weresparged with N2 for 45 minutes. A 3 L round-bottomed flask was charged with potassium phosphate tribasic (92 g, 433 mmol), 1,3-cyclohexanedione (97 weight percent, 20 g, 173 mmol), palladium(II) acetate (0.78 g, 3.5 mmol) and 2-(di-tert-butylphospino)-2?-methylbiphenyl (2.16 g, 6.9 mmol), and the contents were sparged with N2 for 45 minutes. The solution of 1- (benzyloxy)-3-bromobenzene was then transferred to the 1,3-cyclohexanedione mixture via cannula, and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (600 mL) and 10percent hydrochloric acid (600 mL) with mixing. The lower aqueous layer was separated andextracted with ethyl acetate (600 mL). The combined organic layers were washed with brine(2 x 100 mL) and concentrated under reduced pressure. The residue was taken up in toluene(300 mL) and again concentrated under reduced pressure. The residue was taken up intoluene (300 mL) and warmed to 50 °C. After cooling to room temperature, the solids werecollected by filtration, washed with toluene (2 x 50 mL) and dried in a vacuum oven at 50 °Cto give the titled compound (44.6 g, 88percent). ?H NMR (400 MHz, DMSO-d6) oe ppm 10.54 (bs,1H), 7.46?7.28 (m, 5H), 7.19?7.13 (m, 1H), 6.84?6.79 (m, 1H), 6.75 ?6.72 (m, 1H), 6.71?6.66 (m, 1H), 5.03 (s, 2H), 2.76?2.13 (m, 4H), 1.99?1.86 (m, 2H); MS (CT?NH3) m/z 312.0 (M+NH4).
88%
With potassium phosphate; palladium diacetate; di-tert-butyl (2'-methyl-[1,1'-biphenyl]-2-yl)phosphine; In 1,4-dioxane;Inert atmosphere; Reflux;
A 1 L round-bottomed flask was charged with 1-(benzyloxy)-3-bromobenzene (45.5 g, 173 mmol), tert-amyl alcohol (200 mL) and dioxane (400 mL), and the contents were sparged with N2 for 45 minutes. A 3 L round-bottomed flask was charged with potassium phosphate tribasic (92 g, 433 mmol), 1,3-cyclohexanedione (97 weight percent, 20 g, 173 mmol), palladium(II) acetate (0.78 g, 3.5 mmol) and 2-(di-tert-butylphospino)-2?-methylbiphenyl (2.16 g, 6.9 mmol), and the contents were sparged with N2 for 45 minutes. The solution of 1-(benzyloxy)-3-bromobenzene was then transferred to the 1,3-cyclohexanedione mixture via cannula, and the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (600 mL) and 10percent hydrochloric acid (600 mL) with mixing. The lower aqueous layer was separated and extracted with ethyl acetate (600 mL). The combined organic layers were washed with brine (2×100 mL) and concentrated under reduced pressure. The residue was taken up in toluene (300 mL) and again concentrated under reduced pressure. The residue was taken up in toluene (300 mL) and warmed to 50° C. After cooling to room temperature, the solids were collected by filtration, washed with toluene (2×50 mL) and dried in a vacuum oven at 50° C. to give the titled compound (44.6 g, 88percent). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.54 (bs, 1H), 7.46-7.28 (m, 5H), 7.19-7.13 (m, 1H), 6.84-6.79 (m, 1H), 6.75-6.72 (m, 1H), 6.71-6.66 (m, 1H), 5.03 (s, 2H), 2.76-2.13 (m, 4H), 1.99-1.86 (m, 2H); MS (CI?NH3) m/z 312.0 (M+NH4)+.
Magnesium powder (2.8 g) was placed in THF (40 mL).Add 2 iodine,The reaction was heated to 45 C.60111 (20 g) was dissolved in THF (40 mL).Add 1/10 directly to the above reaction solution,After about 10 minutes,Add the remaining solution,After 1 hour of reaction,Cool down to -30 C,After adding CuCN (0.68g),Add S-propylene oxide (8.8g),Raise the temperature to 20 C for 1 hour,Add water to quench the reaction,Dilute with ethyl acetate and filter.Layered,The aqueous phase was extracted again with ethyl acetate.Combine the ethyl acetate layers,After washing with saturated brine,Dry over anhydrous sodium sulfate.filter,After concentration, it was purified by column chromatography to obtain 17.5 g of product.Purity: 98%,Yield: 95%.
74.6%
A solution of the compound obtained in 79-1 (3.37 g, 12.8 mmol) in THF (100 mL) was cooled to -78C, slowly added with n-BuLi (1.6M hexene solution, 8.4 mL, 13.44 mmol), and stirred for 20 minutes. The reaction mixture was added with (S)-(-)propylene oxide (985 L, 14.08 mmol) and BF3·Et2O (2.3 mL, 19.2 mmol), followed by stirring at the same temperature for 1.5 hours. The mixture was added with a saturated NH4Cl aqueous solution, slowly heated to room temperature, and then extracted with EtOAc two times. The oragnic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography to obtain the title compound (colorless oil, 2.3 g, 74.6% yield). (1232) 1H NMR (300 MHz, CDCl3) delta 7.52 - 7.29 (m, 5H), 7.25 - 7.18 (m, 1H), 6.91 - 6.75 (m, 3H), 5.06 (s, 2H), 4.01 (m, 1H), 2.77 (dd, 1H), 2.66 (dd, 1H), 1.51 (d, 1H), 1.24 (d, 3H).
tert-butyl (2S)-2-[3-(benzyloxy)benzoyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
General procedure: Under a nitrogen gas atmosphere, 3-bromoanisole(35 mL, 277 mmol) was added dropwise to a mixtureof magnesium (7.1 g, 292 mmol) and a catalytic amount ofiodine in tetrahydrofuran (THF) (270 mL), and the mixturewas stirred for 2 h. This reaction solution was added dropwiseto a solution of tert-butyl (2S)-2-[methoxy(methyl) amino]-carbonyl}piperidine-1-carboxylate (8, 50.0 g, 184 mmol) inTHF (300 mL) under ice cooling, and the mixture was stirredat room temperature for 2 h. Ten percent aqueous NH4Cl solutionwas added, followed by extraction with EtOAc. Theorganic layer was washed with water and brine, dried overanhydrous Na2SO4, filtered, and concentrated in vacuo. Theresidue was purified using silica gel column chromatography(11percent EtOAc in hexane) to yield 9c (32.7 g, 56percent) as a pale yellowoil.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; caesium carbonate; In methanol; N,N-dimethyl acetamide; water; at 90℃; for 12h;Sealed tube; Inert atmosphere;
Step-2: Synthesis of l-(benzyloxy)-3-(but-l-yn-l-yl)benzene sealed tubc/90 C/12 h To a stirred solution of l-(benzyloxy)-3-bromobenzene (2.5 g, 9.54 mmol) in 30 mL of MeOH:DMA:H20 (1: 1: 1) in a sealed tube, were added copper iodide (0.181 g, 0.95 mmol) and cesium carbonate (4.3 g, 13.3 mmol) at room temperature. This mixture was degassed with three vacuum/N2 cycles, and were added but-l-yn-l-yltrimethylsilane (2.4 g, 19 mmol, Example- 16, Step-2) followed by Pd(PPh3)2Cl2 (0.334 g, 0.479 mmol). The pressure tube was sealed and heated at 90 C for 12 h. Upon completion by TLC, the reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using 1% EtOAc in n-hexane to afford l-(benzyloxy)-3-(but-l-yn-l- yl)benzene (1.6 g, 72%).
To a suspension of magnesium (6 g, 0.25 mol, 3 eq) in dry diethyl ether (30 ml) was added iodine crystal followed by a solution of <strong>[53087-13-1]3-(benzyloxy)phenyl bromide</strong> 3 (22 g, 83.7 mmol) in dry tetrahydrofuran (50 ml) dropwise at a rate (once reaction has initiated), under a nitrogen atmosphere, maintaining a gentle reflux. The resulting mixture was heated at reflux for 1 hour. The mixture was cooled to 0 °C. and a solution of 2-[(dimethylamino)methyl]cyclohexan-1-one 2 (13 g, 83.7 mmol, 1 eq) in dry tetrahydrofuran (50 ml) was added dropwise. The reaction mixture was stirred for 4 hours at RT (room temperature). The reaction mixture was cooled at 0° C and an aqueous solution of ammonium chloride was added dropwise and the resulting suspension was stirred at room temperature overnight. The mixture was filtered through a pad of Celite? and washed with ethyl acetate (3×200 ml). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue obtained was purified by column chromatography (silica gel; 0-50percent ethyl acetate in hexane) to give the title compound (15.75 g) 4 as a yellow oil.
methyl 2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
Step 1: Methyl 2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetate Magnesium turnings (40.9 g, 1.71 mol) were placed in the three necked round bottom flask under argon. Anhydrous THF (1800 mL) and crystals of iodine (6.18 g, 0.024 mol) were added then 1-(benzyloxy)-3-bromobenzene (384.69 g, 1.46 mol) was added in portions. The internal temperature rose to 60° C. and the reaction foamed. The reaction was stirred for 2.5 hours at reflux. In another flask, a solution of methyl benzylformate (200.00 g, 1.22 mol) in anhydrous THF (2000 mL) was cooled to -70° C. under argon and to this the Grignard reagent was added dropwise over 3 hours. The reaction was allowed to slowly warm to room temperature and stirred at this temperature for 18 hours. The reaction was quenched with ammonium chloride solution. Layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were washed with brine and dried over anhydrous magnesium sulfate. The filtrate was evaporated at reduced pressure to afford an oil. The resultant oil was evaporated with hexane twice to afford a solid (473.15 g). The solid was refluxed with 4730 ml hexane (10 ml/g) for 5 min, then allowed to cool to room temperature and stirred for 1 hour, then filtered and washed with hexane to obtain 386.34 g (HPLC: 83.85percent). The product was crystallized in 3930 ml iPrOH (13 ml/g). The mixture was milky at reflux, was filtered (solid: 5.85 g, HPLC: 95.95percent) and the filtrate was allowed to crystallized for 18 hours. The resulting precipitate was stirred for 1.5 hour at 10° C., then filtered and washed with hexane to afford the title product (180.54 g, 42percent). 1H NMR (400 MHz, DMSO-d6); delta 7.44-7.22 (m, 11H), 6.98-6.93 (m, 2H), 6.92-6.88 (m, 1H), 6.68 (s, 1H, OH), 5.05 (s, 2H), 3.70 (s, 3H).
20 g of intermediate 001A, 22.8 g of diaminomesitylene, 14.6 g of t-butoxy sodium and 150 mL of xylene were placed in a 300 mL flask and stirred at room temperature (25 C.) for 30 minutes under a nitrogen atmosphere. Here, 224 mg of palladium acetate and 854 mg of 1,3-bis (2,6-diisopropylphenyl) imidazolinium chloride were added, the mixture was heated and stirred at 150 C. for 1 hour. After the reaction solution was cooled to room temperature, the reaction solution was poured into 500 mL of water and extracted three times with 100 mL of ethyl acetate. The collected organic phases were dried over sodium sulfate, concentrated with an evaporator, and then purified by silica gel chromatography (developing solution: hexane / ethyl acetate = 3/1)17.6 g of Intermediate 001B was obtained as a white solid.
With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; ruphos; In toluene; at 110℃; for 3h;Inert atmosphere; Molecular sieve; Sealed tube;
An oven-dried pressure tube equipped with a magnetic stirringbar was charged with Pd2dba3 (69.6 mg, 1 mol %), RuPhos(35.4 mg, 1 mol %), KOtBu (1.53 g, 13.7 mmol, 1.8 equiv.),1-(benzyloxy)-3-bromobenzene (2 g, 7.6 mmol, 1 equiv.)and activated molecular sieves of 4 A (300 mg). The vesselwas flushed well with argon. Dry toluene (10 mL) and dioctylamine(3.2 mL, 1.4 equiv.) were added, and the pressuretube was sealed with a Teflon screw cap and placedinto an oil bath at 110 C for 3 h. The reaction mixture wasthen cooled to room temperature and filtered. The solventwas removed under reduced pressure and the crude productwas purified by flash chromatography (EtOAc:hexane,1:6), to give the desired product (95%) as a light yellow oil.1H NMR (400 MHz, CDCl3): delta (ppm) 7.49-7.28 (m, 5H),7.10 (dd, J1,2 = 8.0 Hz, 1H), 6.30-6.22 (m, 2H), 5.04 (s,2H), 3.25-3.15 (m, 4H), 1.60-1.48 (m, 4H), 1.35-1.15 (m,20H), 0.88 (t, J = 8.0 Hz, 6H). 13C NMR (100 MHz, CDCl3):delta 160.31, 149.68, 137.66, 129.92, 128.69, 127.95, 127.66,105.24, 100.85, 99.14, 70.02, 51.26, 31.99, 29.66, 29.50,27.41, 27.33, 22.81, 14.26. MS (ESI): m/z calcd. for C29H-46NO: 424.3 (M+H)+, found 424.1.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 7h;Inert atmosphere; Reflux; Large scale;
Compound 2: A flask charged with compound 1 (2818 g, 10.71 mol), (3- fluorophenyl)boronic acid (1574 g, 11.25 mol), and Na2C03 (1135.1 g, 10.71 mol, 1 equiv) was evacuated and refilled with Ar for three times. Deionized water (5.6 L), DME (14 L) and Pd(PPh3)4 (123.8 g, 0.107 mol) were added sequentially. The resulting mixture was degassed and refilled with Ar for three times and then refluxed for 7 h. The suspension was filtered through Celite (500 g) plug. The filtrate was a two-phase mixture. The organic phase was separated. The aqueous phase was extracted with EtOAc (10 L). The combined organic extracts was dried over Na2S04 (3 kg), filtered and concentrated. Half of the crude product was purified by column chromatography (silica gel, eluting with 20% CH2Cl2 in hexanes) to give compound 2 (1040 g, 70% yield) as a white solid.
tert-butyl (R)-(1-(3-(benzyloxy)phenyl)propan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49.5%
Stage #1: 3-(benzyloxy)phenyl bromide With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: (R)-4-methyl-2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylic acid tert butyl ester In tetrahydrofuran at -78 - 0℃; for 1h; Inert atmosphere;
1.1 (R)-(1-(3-(Benzyloxy)phenyl)propyl-2-yl)tert-butyl carbamate 1c
1-benzyloxy-3-bromobenzene 1a (3.65g, 13.91mmol) was dissolved in tetrahydrofuran (40 mL), an argon atmosphere, Stir added n-butyllithium (13.9mmol, 5.8mL), - 78 30 minutes stirring . After 30 minutes, tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide 1b (3.3g, 13.90mmol, using patent application "WO2017182493 "Prepared by the disclosed method) was dissolved in 20 mL of tetrahydrofuran, the above solution was added to the reaction solution, and the reaction was stirred at -78°C for 0.5 hours. When the temperature was slowly raised to 0°C, the reaction was stopped after 30 minutes of stirring under an ice bath. The reaction was quenched with 10% citric acid solution (20 mL), water (100 mL) was added, and the mixture was stirred for 10 minutes. Extract with ethyl acetate (100mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the resulting residue by thin-layer chromatography with the developing solvent system B to obtain the title product 1c (2.37g ), yield: 49.5%.
46%
Stage #1: 3-(benzyloxy)phenyl bromide With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;
Stage #2: (R)-4-methyl-2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylic acid tert butyl ester In tetrahydrofuran at -78 - 0℃; for 1h;
1.1 First step(R)-(1-(3-(Benzyloxy)phenyl)propyl-2-yl)tert-butyl carbamate 1c
Benzyloxy-3-bromobenzene 1a (4.00g, 15.20mmol)Dissolved in tetrahydrofuran (45mL),Argon protection,After stirring well, add n-butyl lithium (15.20mmol, 9.5mL, 1.6M),Stir at -78°C for 30 minutes.Then (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl 2,2-dioxide 1b (3.60g, 15.17mmol,Prepared by the method disclosed in the patent application "WO2016162325, Example 1") dissolved in 20 mL of tetrahydrofuran,Add the above solution to the reaction solution,The reaction was stirred at -78°C for 0.5 hour.When slowly rising to 0,After stirring for 30 minutes under ice bath,Stop the reaction.The reaction was quenched with 10% citric acid solution (20 mL),Add water (100 mL) and stir for 10 minutes.Extract with ethyl acetate (100mL×2),Combine the organic phases,Dry with anhydrous sodium sulfate,filter,The filtrate was concentrated under reduced pressure,Use column chromatography to purify the resulting residue with developing solvent system B,The title compound 1c (2.40g) was obtained,Yield: 46%.
5.6 g
Stage #1: 3-(benzyloxy)phenyl bromide With n-butyllithium In tetrahydrofuran; hexane at -65℃; for 1.5h;
Stage #2: (R)-4-methyl-2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylic acid tert butyl ester In tetrahydrofuran; hexane at -70 - 12℃; for 7h;
tert-butyl 5-(3-(benzyloxy)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium tertiary butoxide In toluene at 110℃; Inert atmosphere;
General procedure A:
General procedure: synthesis of tert-butyl 5-aryl-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solutionof 2, 6- diazaspiro[3.3] heptane- 2- carboxylic acid tert- butylester hemioxylate (0.300 g, 1.23mmol, 1.1 eq.) and an arylbromide (1.12 mmol, 1.0 eq.) in anhydrous toluene (14 mL)under a nitrogen atmosphere was added the following material:Pd2(dba)3 (0.030 g, 2.5mol %), BINAP (0.0450 g, 1.5/Pd),triethylamine (0.125 g, 1.23 mmol, 1.1 eq.) and NaOtBu(0.355 g, 3.69 mmol, 3.3 eq.). The resulting mixture was heatedto 110 °C and stirred overnight under nitrogen. The reactionmixture was cooled to room temperature and then filteredthrough a plug of Celite. The collected filtrate was concentratedunder vacuum to give a crude residue that was further purifiedby column chromatography (hexanes/ethyl acetate, 0-30%).
66%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; sodium tertiary butoxide In toluene at 110℃; Inert atmosphere;
General procedure A:
General procedure: synthesis of tert-butyl 5-aryl-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solutionof 2, 6- diazaspiro[3.3] heptane- 2- carboxylic acid tert- butylester hemioxylate (0.300 g, 1.23mmol, 1.1 eq.) and an arylbromide (1.12 mmol, 1.0 eq.) in anhydrous toluene (14 mL)under a nitrogen atmosphere was added the following material:Pd2(dba)3 (0.030 g, 2.5mol %), BINAP (0.0450 g, 1.5/Pd),triethylamine (0.125 g, 1.23 mmol, 1.1 eq.) and NaOtBu(0.355 g, 3.69 mmol, 3.3 eq.). The resulting mixture was heatedto 110 °C and stirred overnight under nitrogen. The reactionmixture was cooled to room temperature and then filteredthrough a plug of Celite. The collected filtrate was concentratedunder vacuum to give a crude residue that was further purifiedby column chromatography (hexanes/ethyl acetate, 0-30%).
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