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With triethylamine;palladium diacetate; 1,3-bis-(diphenylphosphino)propane; at 100℃; under 25858.1 Torr; for 15h;
30. 0g (139 mmol) of (4-Bromo-phenyl) -acetic acid 5.7g (14 mmol) DPPP, 32.4 mL of triethylamine, 2.08 g palladium acetate and 300 mL of methanol were introduced into a vessel. The vessel was sealed and pressurized with carbon monoxide to a pressure of [500PSI.] The vessel was heated at 100 [C] for 15 hours. The mixture was then cooled and concentrated on a rotary evaporator before partitioning between EtOAc and 2M [HC1.] Separated and extracted the aqueous layer with EtOAc [(LX).] The organic extracts were combined and washed with saturated aqueous [NACL] solution and dried [(MGS04).] Concentration provided a solid which was slurred in hexane and filtered. The material was dried in a vacuum oven at-10mmHg at [70 C] ; yield 24 g [(88%)] MS: m/z (APCI, AP-) 179 [[M']-] NMR: DMSO 1H 8 (ppm) 3.86 (3H, s); 7.63-7. 67 [(1H,] m); 8. [15- 8.] 18 (2H, m); 8.45-8. 46 (1H m).
76%
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 120℃; under 30003.0 Torr; for 16h;
To a solution of 2-(4-bromophenyl)acetic acid (B-1) (91.3 g, 0.42 mol, 1.0 eq) in MeOH (1.5 L) was added dry TEA (85.8 g, 0.85 mol, 2.0 eq) and Pd(dppf)Cl2 (3.43 g, 4.2 mmol, 1%). The solution was heated under CO gas (4 MPa) at 120C for 16 h. Then it was filtered and concentrated in vacuo. The residue was dissolved in 500 mL of EA and 1 L of water. The mixture was neutralized by sat. NaHC03 to pH = 7.5 and separated. The inorganic phase was extracted with EA (500 mL x 3) acidified with IN HC1 to pH = 5. Filtration and drying in vacuo afforded 62.8 g of B-2 (white solid, yield 76%). MS (ESI): m/z 195.1 [M+l]+.
76%
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 120℃; for 16h;
Intermediate A: 4-(2-(2,4-dihydroxyphenyl)-2-oxoethyl)benzamide[00213] Step 1: Synthesis of 2-(4-(methoxycarbonyl)phenyl)acetic acid. To a solution of 2- (4-bromophenyl) acetic acid (91.3 g, 0.42 mol, 1.0 eq.) in MeOH (1.5 L) was added dry TEA (85.8 g, 0.85 mol, 2.0 eq.) and Pd(dppf)Cl2 (3.43 g, 4.2 mmol, 1%). The solution was heated under CO gas (4 MPa) at 120 C for 16 hours. Then it was filtered and concentrated in vacuo. The residue was dissolved in 500 ml of EtOAc and 1 L of water. The mixture was neutralized by sat. NaHC03 to pH = 7.5 and separated. The inorganic phase was extracted with EtOAc (500 ml x 3) acidified with IN HC1 to pH = 5. Filtration and drying in vacuo afforded 62.8 g of product (white solid, yield 76%). MS (ESI): m/z 195.1 [M+l]+.
2-(4-bromophenyl)-1-(3,3-difluoropiperidin-1-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 17h;
To 4-bromophenylacetic acid (4g; 18.6mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (2.5g; 20.4mmol) in methylene chloride (190mL) solution, add EDC (3.8g; 22.3 mmol), HOBt (3g; 22.3mmol) and triethylamine (1.3mL; 593mmol). The reaction mixture was stirred at ambient temperature for 17 hours, then poured onto a mixture of aqueous sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate. With 0.1N hydrochloric acid, water and brine the organic phase, then dried with MgSO4, and concentrated to dryness. Purification by silica gel chromatography of the residue (petroleum ether / ethyl acetate gradient), to give the desired product as a solid.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 17h;
Step A: 2-(4-Bromophenyl)-1-(3,3-difluoropiperidin-1-yl)ethanone (0234) To a solution of 4-bromophenylacetic acid (4 g; 18.6 mmol) and <strong>[496807-97-7]3,3-difluoropiperidine hydrochloride</strong> (2.5 g; 20.4 mmol) in dichloromethane (190 mL) there are added EDC (3.8 g; 22.3 mmol), HOBt (3 g; 22.3 mmol) and triethylamine (1.3 mL; 593 mmol). The reaction mixture is stirred for 17 hours at ambient temperature and is then poured over a mixture of aqueous sodium bicarbonate and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with 0.1N hydrochloric acid, with water and with brine before being dried over MgSO4 and concentrated to dryness. The residue is purified by chromatography over silica gel (petroleum ether/ethyl acetate gradient) to provide the expected product in the form of a solid. (0235) 1H NMR: delta (400 MHz; dmso-d6; 300K): 7.5 (d, 2H); 7.2 (d, 2H); 3.8 (t, 2H); 3.7 (s, 3H); 3.5 (t, 2H); 2 (m, 2H); 1.6 (m, 2H)