Structure of 1613192-96-3
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CAS No. : | 1613192-96-3 |
Formula : | C5H3BrCl2FN |
M.W : | 246.89 |
SMILES Code : | FC1=CN=CC(Br)=C1Cl.[H]Cl |
MDL No. : | MFCD28805788 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41 g | With sodium hydroxide In dichloromethane for 1 h; Cooling with ice | [ 0505] 3 -bromo-4-chloro-5-fluoro-pyridine hydrochloride18 ( 62 g, 251.1 mmol) was suspended in DCM ( 600 mL) andstirred. The mixture was cooled in an ice bath and sodiumhydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly.The resulting mixture was stirred for 1 hour. The mixture wasphase-separated. More DCM/water was added to aid phaseseparation. Some tarry particulates remained in the aqueousphase. The organic phase was washed with brine, dried(MgS04 ), filtered and concentrated. The residue was trituratedwith heptane. The heptane solution was filtered througha florsil pad, eluting with heptane. The filtrate was concentratedto an oil which solidified. This gave 41 g offree base. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | 3-bromo-4-chloro-5-fluoro-pyridine hydrochloride 18 (62 g, 251.1 mmol) was suspended in DCM (600 mL) and stirred. The mixture was cooled in an ice bath and sodium hydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly. The resulting mixture was stirred for 1 hour. The mixture was phase-separated. More DCM/water was added to aid phase separation. Some tarry particulates remained in the aqueous phase. The organic phase was washed with brine, dried (MgS04), filtered and concentrated. The residue was triturated with heptane. The heptane solution was filtered through a florsil pad, eluting with heptane. The filtrate was concentrated to an oil which solidified. This gave 41g of free base. [00384] A thoroughly stirred mixture of 3-bromo-4-chloro-5-fluoropyridine free base (55 g, 0.26 mol), potassium fluoride (31 g, 0.53 mol) and Me4NCl (5.8 g, 53 mmol) in DMSO (400 mL) was heated to 130°C for 2 hours. The reaction mixture was cooled to room temperature and <strong>[892493-65-1]tert-butyl piperidine-4-carboxylate hydrochloride</strong> 22 (66 g, 0.30 mol) and DIPEA (65 g, 0.50 mol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was portioned between DCM/water. The organic layer was washed with water (3x), dried over Na2S04, and filtered over silica gel using DCM as eluent. The filtrated was evaporated to give tert-butyl l-(3-bromo-5- fluoropyridin-4-yl)piperidine-4-carboxylate 26 (61g, 65percent) as a light yellow solid; 1H NMR (500 MHz, DMSO-i/6) delta 8.47 (s, 1H), 8.41 (d, 1H), 3.39 - 3.36 (m, 2H), 3.12 (tt, 2H), 2.49 - 2.43 (m, 1H), 1.91 - 1.87 (m, 2H), 1.71 - 1.64 (m, 2H) and 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6) delta -135.2; MS (ES+) 361.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrogenchloride; In diethyl ether; pentane; for 0.0833333h; | To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20C then cooled back down to -78C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70C (approx 30 mins). The reaction mixture was stirred at - 78C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 niL) was then added dropwise, keeping temperature below -70C (over approx 30 mins). The mixture was stirred at -78C for 20 minutes, allowed to warm to room temperature, cooled back to 0C and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown011 that turned to a crystalline solid on standing, 11.85 g, 89%). XH NMR (DMSO-d6) delta 8.78 (s, 1H), 8.76 (s, 1H). [00372] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60%). XH NMR (DMSO-d6) delta 8.77 (s, 1H), 8.75 (s, 1H). |
60% | With hydrogenchloride; In diethyl ether; pentane; for 0.0833333h; | Preparation 9: (l-(3-amino-5-fluoropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-l- yl)methanone (hydrochloride) 17 Scheme 4 Step 1: <strong>[1211540-92-9]3-bromo-4-chloro-5-fluoropyridine</strong> hydrochloride 18 [00264] To a solution of diisopropylamine (6.899 g, 9.555 mL, 68.18 mmol) in THF (75 mL) cooled to -78C, was added butyllithium (25 mL of 2.5 M in hexanes, 62.5 mmol). The reaction mixture was allowed to warm to -20C then cooled back down to -78C. A solution of 3-bromo-5-fluoro-pyridine (10 g, 56.82 mmol) in THF (25 mL) was added dropwise keeping temperature below -70C (approx 30 mins). The reaction mixture was stirred at - 78C for 30 min and a solution of 1, 1, 1,2,2,2-hexachloroethane (14.8 g, 62.5 mmol) in THF (20 mL) was then added dropwise, keeping temperature below -70C (over approx 30 mins). The mixture was stirred at -78C for 20 minutes, allowed to warm to room temperature, cooled back to 0C and quenched with water (100 mL). EtOAc (400 mL) was then added, and organic layer separated, washed with water (2x), brine (lx), dried (MgS04), filtered and concentrated in vacuo to leave a brown solid. The solid was triturated in pentane (lOOmL) for 10 minutes, then filtered. The filtrate was concentrated in vacuo to afford product as a brown 011 that turned to a crystalline solid on standing, 11.85 g, 89%). 1H NMR (DMSO-d6) delta 8.78 (s, 1H), 8.76 (s, 1H). [00265] To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60%). 1H NMR (DMSO-d6) delta 8.77 (s, 1H), 8.75 (s, 1H). |
60% | With hydrogenchloride; In diethyl ether; pentane; | To a solution of 3-bromo-4-chloro-5-fluoro-pyridine (7.56 g, 32.18 mmol) in pentane (100 mL) was added hydrogen chloride (2M in ether) (17.7 mL of 2 M, 35.4 mmol). An off-white precipitate formed instantly. The mixture was stirred for 5 minutes then the solid was collected by filtration, washed with pentane and dried by suction to afford the desired product as an off-white solid (4.79 g, 60%). ?H NMR (DMSO-d6) oe 8.77 (s, 1H), 8.75 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium carbonate; In cyclohexanol; at 120℃; for 18h;Inert atmosphere; | A 3L flange flask equipped with a thermometer, condensor, nitrogen line and overhead stirrer was heated at 40°C (external) then charged with cyclohexanol (750 mL), disodium carbonate (129.8 g, 1.225 mol), 3-bromo-4-chloro-5-fluoro-pyridine (Hydrochloric Acid 18) (137.5 g, 556.8 mmol) and <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong> (123.8 g, 668.2 mmol) rinsed in with cyclohexanol (350 mL). Mixture was heated to 120°C internal temperature overnight (18h). Reaction mixture was removed from hotplate and allowed to cool to room temperature. Water (687.5 mL) and EtOAc (687.5 mL) were added, stirred for 10 mins then transferred to separating funnel. Additional EtOAc (1.238 L) was added, mixed and aqueous phase was removed. Organic phase was further washed with water (687 mL), aqueous phase removed, organic layer collected. Aqueous phases were combined and back extracted with EtOAc (687.5 mL), aqueous layer removed and organic phase combined with other organics. Organics concentrated in vacuo (water bath temp = 60°C, vaccum down to 2 mBar) leaving a viscous brown oil. [00379] Oil was dissolved in 25percent EtO Ac/petrol then passed through a short silica pad, eluting with 25percent EtOAc/petrol until no more product came off. Filtrate was concentrated in vacuo to leave a brown oil, 127. lg. Product re-purified by ISCO companion (1.5Kg Silica, loaded in DCM, eluting 0 to 20percent EtO Ac/petrol), product fractions combined and concentrated in vacuo to leave desired product 26 as a pale yellow to cream solid, (98g, 49percent yield). 'H NMR (500 MHz, DMSO-d6) delta 8.47 (s, 1H), 8.41 (d, 1H), 3.39 - 3.36 (m, 2H), 3.12 (tt, 2H), 2.49 - 2.43 (m, 1H), 1.91 - 1.87 (m, 2H), 1.71 - 1.64 (m, 2H) and 1.43 (s, 9H). MS (ES+) 361.0. |
49% | With sodium carbonate; In cyclohexanol; at 40 - 120℃;Inert atmosphere; | [0499] A 3 L flange flask equipped with a thermometer,condenser, nitrogen line and overhead stirrer was heated at40° C. (external) then charged with cyclohexanol (750 mL),disodium carbonate (129.8 g, 1.225 mol), 3-bromo-4-chloro-5-fluoro-pyridine (Hydrochloric Acid 18) (137.5 g, 556.8mmol) and <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong> (123.8 g,668.2 mmol) rinsed in with cyclohexanol (350 mL). Mixturewas heated to 120° C. internal temperature overnight (18 hr.).Reaction mixture was removed from hotplate and allowed tocool to room temperature. Water (687.5 mL) and EtOAc( 687.5 mL) were added, stirred for 10 mins then transferred toseparating funnel. Additional EtOAc (1.238 L) was added,mixed and aqueous phase was removed. Organic phase wasfurther washed with water ( 687 mL ), aqueous phase removed,organic layer collected. Aqueous phases were combined andback extracted with EtOAc (687.5 mL), aqueous layerremoved and organic phase combined with other organics.Organics concentrated in vacuo (water bath temp=60° C.,vacuum down to 2 mBar) leaving a viscous brown oil.[0500] Oil was dissolved in 25percent EtOAc/petrol then passedthrough a short silica pad, eluting with 25percent EtOAc/petroluntil no more product came off. Filtrate was concentrated invacuo to leave a brown oil, 127.1 g. Product re-purified byISCO companion (1.5 Kg Silica, loaded in DCM, eluting 0 to20percent EtOAc/petrol), product fractions combined and concentratedin vacuo to leave desired product 26 as a pale yellow tocream solid, (98 g, 49percent yield). 1 H NMR (500 MHz, DMSOd6)o 8.47 (s, lH), 8.41 (d, lH), 3.39-3.36 (m, 2H), 3.12 (tt,2H), 2.49-2.43 (m, lH), 1.91-1.87 (m, 2H), 1.71-1.64 (m, 2H)and 1.43 (s, 9H). MS (ES+) 361.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41 g | With sodium hydroxide; In dichloromethane; for 1h;Cooling with ice; | [ 0505] 3 -bromo-4-chloro-5-fluoro-pyridine hydrochloride18 ( 62 g, 251.1 mmol) was suspended in DCM ( 600 mL) andstirred. The mixture was cooled in an ice bath and sodiumhydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly.The resulting mixture was stirred for 1 hour. The mixture wasphase-separated. More DCM/water was added to aid phaseseparation. Some tarry particulates remained in the aqueousphase. The organic phase was washed with brine, dried(MgS04 ), filtered and concentrated. The residue was trituratedwith heptane. The heptane solution was filtered througha florsil pad, eluting with heptane. The filtrate was concentratedto an oil which solidified. This gave 41 g offree base. |
Tags: 1613192-96-3 synthesis path| 1613192-96-3 SDS| 1613192-96-3 COA| 1613192-96-3 purity| 1613192-96-3 application| 1613192-96-3 NMR| 1613192-96-3 COA| 1613192-96-3 structure
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