| 99% |
With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); bis[2-(diphenylphosphino)phenyl] ether; In toluene; at 0 - 100℃; for 0.416667 - 3.08333h;Product distribution / selectivity; |
Example 17; C20 g 2-bromoiodobenzene (71 mmol) and 9.8 g 2,4-dimethylthiophenol (71 mmol) were dissolved in 100 ml toluene. The solution was purged with nitrogen before 324 mg Pd2dba3 (0.35 mmol; 1 mol-%) and 381 mg DPEPhos (0.71 mmol; 1 mol-%). The reaction mixture was stirred 5 min during which the colour changes from dark-red to orange. Addition of 8.7 g KOBu' (78 mmol) took place and a heterogeneous mixture was formed instantly. The suspension was heated to 100 0C under nitrogen. After 1 hour the mixture was cooled to 0 0C and stirred for 2 hours before filtering the mixture though a pad of celite. The filter cake was washed with 2 x 50 ml toluene and the combined filtrates evaporated to 21 g of a orange-reddish oil (99 % yield) that proved > 96 % pure on HPLC and GC-MS.; Example 22; 500 ml toluene was placed in a IL three-necked round bottle with a mechanical stirrer and added 809 mg Pd2dba3 (0.88 mmol; 0.5 mol-%) and 952 mg DPEPhos (1.77 mmol; 0.5 mol-%). The dark-red solution was purged with nitrogen for 5 minutes before addition of 100 g 2-bromoiodobenzene (353 mmol) and 48.9 g 2,4- dimethylthiophenol (353 mmol) took place. Addition of 43.6 g KOBu' (389 mmol) caused an exothermic reaction increasing the temperature from 20 0C to 42 0C simultaneously with the formation of a heterogeneous mixture and the colour changed from dark-red into orange/brownish. The suspension was heated to 100 0C under nitrogen. After only 20 minutes a HPLC showed full conversion into l-(2-Bromo- phenylsulfanyl)-2,4-dimethyl-benzene. The mixture was cooled to 40 0C, added 600 <n="48"/>ml 15-wt% NaCl and stirred for 5 minutes. The organic phase was separated and the aqueous phase was washed with 2 x 100 ml toluene. The combined organic phases were washed with 100 ml 2M HCl (aq.), 100 ml 15-wt% NaCl, dried over Na2SO4, refiuxed for 15 minutes with activated charcoal (10 g), filtered twice and evaporated to 107.3 g orange-red oil (103 %) that was found to be 98 % pure by HPLC.A solution of 90 gram of the orange-red oil (307 mmol) in 500 ml dry toluene was added 57 gram boc-piperazine (307 mmol), degassed with nitrogen for 5 minutes, added 1.4 g Pd2dba3 (1.53 mmol; 0.5 mol-%) and 2.9 g ralphac-BINAP (4.6 mmol; 1.5 mol-%), degassed for another 2 minutes before adding 35.4 gram Bu1ONa (368 mmol) and heated to 80 0C for 18 hours. HPLC showed full conversion and the reaction mixture was cooled to RT, filtered and the filter cake was washed with 2 x 100 ml toluene. The combined filtrates was extracted twice with 2 x 150 ml 15-wt% NaCl, dried over Na2SO4, added charcoal, refiuxed for 30 minutes, filtered twice and evaporated to 140.7 gram of brownish oil (4-[2-(2,4-Dimethyl-phenylsulfanyl)- phenyl]-BOC-piperazine). The crude oil was dissolved in 300 ml MeOH and 200 ml 6M HCl (aq.) and refiuxed for 1 hour after which HPLC showed full deprotection. After cooling to RT the methanol was removed by vacuum on a rotary-evaporator, 200 ml cone. NaOH (pH was measured to 13-14) was added after which the mixture was stirred 15 minutes with 1000 ml EtOAc. The organic phase was collected and extracted with 300 ml 15-wt% brine, dried over Na2SO4 and added to a solution of 46.3 g fumaric acid (399 mmol) in 300 ml MeOH. The mixture was heated to reflux, cooled to room temperature and then left in the freezer overnight (-18 0C). The precipitate was collected, washed with 100 ml EtOAc and 100 ml acetone, dried in vacuum (50 0C) producing 103.2 g of l-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]- piperazine fumarate (249 mmol) as a white powder in 81 % overall yield having a purity of 99 % by LC-MS. The fumarate was transfer into the free base (l-[2-(2,4- Dimethyl-phenylsulfanyl)-phenyl]-piperazine) using EtOAc/H2O/conc. NaOH, the organic phase was washed with brine, dried using Na2SO4, filtered and to the filtrate was added 34 ml 48-wt% HBr (aq.) causing a precipitation of a white solid. The solid was collected, treated with 1000 ml boiling H2O, which upon cooling to room temperature formed a slurry. The final product (l-[2-(2,4-Dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide) was collected by filtration and dried in vacuum (50 <n="49"/>0C) producing 83 g of white powder (71 % yield overall), CHN (teo.) 56.99; 6.11; 7.39; CHN (found) 57.11; 6.15; 7.35. |
| 98.2% |
With copper(l) iodide; potassium tert-butylate; In isopropyl alcohol; for 12h;Inert atmosphere; Reflux; |
2-Bromoiodobenzene (formula II) (50.0 g, 177 mmol) was dissolved in 500 ml of isopropanol,Add 2,4-dimethylthiophenol (formula III) (29.3 g, 212 mmol),Cuprous iodide (3.37g, 17.7mmol),Potassium tert-butoxide (39.7 g, 354 mmol).Heat to reflux under nitrogen and react for 12 h.After the reaction was completed, it was cooled to room temperature and filtered.The isopropanol was removed under reduced pressure, and 1000 ml of dichloromethane and 1000 ml of purified water were added thereto, followed by extraction.The aqueous layer was extracted once with 1000 ml of dichloromethane.The combined dichloromethane layer was washed with saturated brine.dry. Dichloromethane is removed under reduced pressure.Intermediate 4 (formula IV) 49.6g,The yield was 98.2%. |
| 72.4% |
With copper(l) iodide; 2-acetylcyclohexanone; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; |
A mixture of 1.7 g of compound A, 2.8 g of compound B, 0.4 g of cuprous iodide and 2.8 g of 100 to 200 mesh potassium carbonate was weighed into a 100 mL three-necked flask, and 50 mL of DMF was added to the flask. After stirring, 0.6 g of 2-acetylcyclohexanone was added After heating, the mixture was heated to 80 C and reacted for 2 hours. The reaction was monitored by TLC. After the completion of the reaction, 100 mL of ethyl acetate and 150 mL of water were added. The filtrate was separated by suction filtration, and the organic phase was washed twice with 100 mL of 0.1N sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulphate for 2 h and concentrated at 45 C to give an oil. After 40 mL of petroleum ether was added to the oil, the mixture was stirred for 3 h, filtered and the filter cake was washed twice with a little solvent. And dried in vacuo for 12 h to give 2.1 g of the product as a pale yellow solid. The yield was 72.4%. |
|
With potassium phosphate; copper(l) iodide; L-proline; In N,N-dimethyl-formamide; at 70 - 80℃; for 5h;Inert atmosphere; |
Under nitrogen protection, In a 500-mL reactor were charged 13.8 g (0.1 mol) The compound of the formula (4) 2,4-dimethylthiophenol, 28.3 g (0.1? Bromoiodobenzene, 53.0 g (0.25 mol) Potassium phosphate and 1. 9 g (0. Olmol) Cuprous iodide, 1.15 g (0.01 mol) L-proline, 300 mL of dimethylformamide was added, Stirring heated to 70-80 C, Reaction 5h, After completion of the reaction, To the reaction solution, 9. 46 g (0.11 mol) Piperazine, Heating was continued for 5-8 hours, After completion of the reaction, a portion of the solvent was distilled off. The residue was added with water and extracted three times with 300 ml of methylene chloride. The organic layers were combined, dried and evaporated to give methylene chloride. The residue was recrystallized from 200 mL of acetonitrile to give 28.8 g of a white solid, yield 96.7%, purity 99.2% (HPLC): Luna Phenyl-Hexyl column (4.6 mm × 150 mm, 3 um) was used as the mobile phase. The mobile phase consisted of 0 · 05% trifluoroacetic acid (60:40) Temperature 40 C; flow rate lml / min]. |
|
With sodium t-butanolate;2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); In toluene; at 100℃;Product distribution / selectivity; |
Example 21; 102 g 2-bromo-iodobenzene (362 mmol) and 50 g 2,4-dimethylthiophenol (362 mmol) are dissolved in 1000 ml toluene. To this solution was added 81 g BOC- piperazine (434 mmol) followed by 2.08 g Pddba2 (1 mol%) and 4.51 g rac-BINAP (2 mol%). The mixture was purged with nitrogen for 5 minutes before adding a slurry of 87 g NaOBu' (905 mmol) in 300 ml toluene. The suspension was heated to 100 0C under nitrogen overnight. A GCMS analysis showed full conversion into the intermediate product (l-(2-Bromo-phenylsulfanyl)-2,4-dimethyl-benzene) and the temperature was increased to reflux (120 0C) for another 24 hours. A HPLC analysis showed full conversion into the intermediate (l-BOC-4-[2-(2,4-Dimethyl- <n="47"/>phenylsulfanyl)-phenyl]-piperazine). The reaction mixture was cooled on ice for one hour before filtering the mixture. The filter cake is washed with 2 x 200 ml toluene and to the combined filtrates was added 80 ml 48-wt% HBr (aq.) followed by heating to reflux for 18 hours after which full deprotection was detected by HPLC. The mixture was cooled on ice for 2 hours and filtrated. The brownish solid was dissolved in 1000 ml boiling H2O for 1 hour together with activated charcoal (25 g), filtered while hot and left to cool. The precipitate was collected by filtration and drying in vacuum at 40 0C overnight produced 49 g of 4-[2-(2,4-Dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide (36 %) as a white solid. |
|
With sodium t-butanolate;2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; bis(dibenzylideneacetone)-palladium(0); In toluene;Heating / reflux;Product distribution / selectivity; |
Example 24; 40,76 g NaOBu (424,lmol), 0,33 g Pddba2 (0,57 mmol) and 0,68 g rac-BINAP (1,09 mmol) were stirred with 200 ml toluene. 42 g 2-bromo-iodobenzene (362 mmol) and 19,54 g 2,4-dimethylthiophenol (362 mmol) were added with 50 ml toluene. The suspension was heated to reflux and reflux continued over night. A HPLC analysis showed full conversion into the intermediate product (l-(2-Bromo-phenylsulfanyl)- <n="50"/>2,4-dimethyl-benzene). The reaction mixture was cooled to RT and filtered through filter aid. The filtrate was added to a mixture of 40,76 g NaOBu' (424,1 mmol), 42,2 g piperazine (489,9 mmol), 0,33 g Pddba2 (0,57 mmol) and 0,68 g rac-BINAP (1,09 mmol) and heated to reflux for 2 hours. The reaction mixture was cooled down over night. 100 ml water was added and the water phase separated off. The organic phase was filtered through filter aid and the filtrate was then washed with 3x 80ml brine. The combined water phases were then extracted with 50 ml toluene. The combined toluene phases were then heated to 700C and followed by addition of 16,5 ml 48-wt% HBr (aq.) and 8,25 ml water. The mixture was cooled to room temperature over night. The final product (l-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried in vacuum (60 0C) producing 40,18 g of off-white powder (75 % yield); Example 25; 40,76 g NaOBu (424,lmmol), 0,33 g Pddba2 (0,57 mmol) and 0,68 g rac-BINAP (1,09 mmol) were stirred with 200 ml toluene. 42 g 2-bromo-iodobenzene (148,5 mmol) and 19,54 g 2,4-dimethylthiophenol (141,4 mmol) was added with 50 ml toluene. The suspension was heated to reflux and reflux continued over night. A HPLC analysis showed full conversion into the intermediate product (l-(2-Bromo- phenylsulfanyl)-2,4-dimethyl-benzene). Reaction cooled to 500C and 42,2 g piperazine (489,9 mmol) was added along with 100 ml toluen. The mixture was heated to reflux for 4 hours. The reaction mixture was cooled to RT over night. 100 ml water was added and the reaction mixture was filtered through filter aid. The filter cake was then washed with 50 ml toluen.The water phase was separated off and the organic phase was then washed with 3x 25 ml brine and 25 ml water. The combined water phases was then extracted with 30 ml toluene. The combined toluene phases was then heated to 700C and followed by addition of 16,46 ml 48-wt% HBr (aq.) and 8,23 ml water. The mixture <n="51"/>was cooled to room temperature over night. The final product (l-[2-(2,4-Dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide) was collected by filtration and dried in vacuum (60 0C) producing 46,8 g (87 % yield). |
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