| 74.7% |
With copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 120℃; for 12h; |
5g (23 · 9mmol) of 9,9-dimethylacridine and 7.4g (26.3mmol) of 4-bromoiodobenzene were mixed.457 mg (2.4 mmol) of cuprous iodide was added,Then add 50ml of NMP,Stir and heat at 120C for 12 hours.After cooling to room temperature, the mixture was filtered, and the filtrate was poured into 500 ml of water and filtered. The filter cake was washed with water to give a white solid, which was recrystallized from ethanol to give 6.5 g of a white solid. The yield was 74.7%. |
| 74% |
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; for 3h;Inert atmosphere; Reflux; |
S7 (2.5 mmol), S8 (2.6 mmol), (dibenzylideneacetone) dipalladium (0) (0.12 mmol),Sodium tert-butoxide (4 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.25 mmol) were put into a 100 mL three-necked flask,While stirring, degassing and nitrogen replacement were repeated 3 times quickly, and 40 mL of toluene was added via a syringe.The mixture was heated under reflux under a stream of nitrogen for 3 hours.After the reaction, water was added to the reaction solution cooled to room temperature, extraction was performed with dichloromethane, and the solution was washed with saturated brine.After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off and purified by column chromatography.Intermediate S9 (1.85 mmol, 74%) was obtained. |
| 70% |
With tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; sodium t-butanolate; In toluene; at 70 - 105℃; for 12h;Inert atmosphere; Reflux; |
Under the protection of nitrogen, add 9,9-dimethylacridine 50mmol, p-bromoiodobenzene 50mmol, toluene 105mL and 100mmol sodium tert-butoxide to the reaction flask, stir and heat to 70-80 , then quickly add three 5 mmol of tert-butylphosphine in toluene solution and 10 mmol of Pd2 (dba) 3. After the addition, the temperature was continuously raised to 100-105 C and the reaction was refluxed for 12 hours. After the reaction was completed, the temperature was lowered, and the organic phase was extracted with water, washed, dried, and filtered. concentrate. After passing through the column with a mixed solvent of dichloromethane and n-heptane, it was recrystallized to LC> 99.5%, and dried to obtain compound 10- (4-bromophenyl) -<strong>[6267-02-3]9,9-dimethyl-9,10-dihydroacridine</strong>. , Ie intermediate 1 (yield 70%). |
| 65.8% |
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In toluene; at 80℃; for 20h;Inert atmosphere; |
4.0 g (11.12 mmol) of <strong>[6267-02-3]9,9-dimethyl-9,10-dihydroacridine</strong> was weighed2.44 ml (5.40 g, 11.12 mmol) of bromoiodobenzene,3.98 g (38.24 mmol) of anhydrous sodium tert-butoxide,1.46 ml (0.58 mmol) of tri-tert-butylphosphine,0.086 g (0.38 mmol) of palladium acetate in a 250 mL three-necked flask,Then, 100 mL of anhydrous toluene was added as a reaction solvent.Under nitrogen protection,And the mixture was heated to 80C for 20 hours.After completion of the reaction,After the solvent was removed under reduced pressure, dichloromethane (100 mL × 3) was added to extract the reaction solution,The extracts were combined and dried over anhydrous magnesium sulfate,Spin dry solvent.The crude product was purified by column chromatography using petroleum ether and methylene chloride (PE: DCM = 15: 1)4.56 g of a white crystalline powder was obtained,The yield was 65.8%. |
| 65.7% |
With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate; In tetrahydrofuran; at 80℃; for 20h;Inert atmosphere; |
Weigh 2.0 g (9.56 mmol) of <strong>[6267-02-3]9,9-dimethyl-9,10-dihydroacridine</strong>, 2.70 g (9.56 mmol) of bromoiodobenzene, 18.4 g (191.2 mmol) of anhydrous sodium tert-butoxide, 0.73 ml (0.29 mmol) of tri-tert-butylphosphine, 0.043 g (0.19 mmol) of palladium acetate in a 250 mL three-necked flask, Then 100 mL of dry tetrahydrofuran was added as the reaction solvent. Under nitrogen, heated to 80 C for 20 hours. After the reaction, The reaction solution was extracted with dichloromethane (50 mL x 3) after solvent extraction, The extracts were combined and dried over anhydrous magnesium sulfate, dried to dry the solvent and dried. The crude product was treated with petroleum ether and dichloromethane (PE:DCM=15:1) And the residue was purified by column chromatography to obtain 2.28 g of white crystalline powder, Yield 65.7%. |
| 63% |
With tri-tert-butylphosphonium tetrafluoroborate; palladium diacetate; caesium carbonate; In toluene; at 130℃; for 12h;Inert atmosphere; |
A three-necked flask was charged with 9,9-dimethylacridine (1 g, 4.78 mmol), p-bromoiodobenzene (1.48 g, 5.26 mmol), palladium acetate (0.14 g, 0.15 mmol), and cesium carbonate (3.89 g, 11.93 mmol), tri-tert-butylphosphine tetrafluoroborate (0.044 g,0.15 mmol), added to 30 mL of dry toluene, and heated to 130 C for 12 h under the protection of nitrogen. After the reaction, the reaction solution was poured into saturated brine, and then subjected to liquid separation extraction with dichloromethane and ethyl acetate, and the solvent was distilled off under reduced pressure. The crude product was subjected to column chromatography to obtain intermediate M3 with a yield of 63%. . |
| 60% |
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 24h;Inert atmosphere; Reflux; |
Under nitrogen protection(14 gg, 0.05 mol) and 9,9 '-dimethylacridine (l (K45g, 0.05piomicron1) were dissolved in 100 mL of DMF under nitrogen atmosphere, And then put the catalyst copper (3.2 g, 27 mmol) and acid addition of potassium carbonate (13.8 g, 0.1 mol),. The system was heated to reflux for 24 hours. After cooling to room temperature, 500 mL of water was added to quench the reaction. The product was filtered to give crude product. The crude product was purified by silica gel column chromatography and the eluent was purified by purification with V ethyl acetate: V n-hexane = 1: 6 to give an off-white powder in a yield of 60%. |
| 53% |
With 1,10-Phenanthroline; copper(l) chloride; potassium hydroxide; In toluene; at 120℃; for 24h;Inert atmosphere; |
9,9-Dimethyl acridine (5.0 g, 24.7 mmol), 2-bromo-5-iodobenzene (9.06 g, 32·1 mmol), cuprous chloride (489) were sequentially added to a 250 mL single-mouth bottle. Mg, 4.94 mmol), potassium hydroxide (6·92 g, 124 mmol), 1,10-phenanthroline (891 mg, 4.94 mmol) and 130 mL of toluene, and the mixture was stirred at 120 C for 24 h under nitrogen. The reaction solution was cooled to room temperature, extracted with dichloromethane (3×30 mL). The organic layer was washed with brine (3×30 mL), dried, filtered, and evaporated to remove solvent. A white solid was obtained in 4.78 g, yield 53%. |
| 50% |
|
In a 50 mL three-necked flask, 2.09 g (10.00 mmol) of 9,9-dimethylacridine, 3.11 g (11.00 mmol) of 1-bromo-4-iodobenzene, 1.92 g (20.00 mmol) of NaOtBu, 4-Dioxane (20 mL) was added and the mixture was nitrogen-flowed for 1 hour. Thereafter, 40 mg (0.20 mmol) of CuI and 110 mg (1.00 mmol) of L-proline were added and heated to reflux. After 18 hours, the formation of the target product was confirmed by TLC and MS measurement, and the reaction was stopped. Thereafter, the reaction solution was added to 200 mL of water, extracted three times with 100 mL of toluene, dehydrated with sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 1.82 g (yield 50%) of a white solid. |
| 21% |
With potassium carbonate; rac-diaminocyclohexane; copper(l) chloride; In dimethyl sulfoxide; at 110℃; for 16h;Inert atmosphere; |
9,10-Dihydro-9,9-dimethylacridine (25.0 g, 119.6 mmol), 1-bromo-4-iodobenzene (38.0 g, 134.3 mmol), cuprous chloride (I) (2.37 g, 23.9 mmol), dimethyl sulfoxide (250 ml), potassium carbonate (33.1 g, 239.2 mmol) and 1,2-diaminocyclohexane (6.8 g, 59.8 mmol). A 500 ml double neck round bottom reaction flask was added, and the reaction system was filled with nitrogen. The system was heated to 110 C in an oil bath. After 16 hours of reaction, the system was cooled and the reaction was poured into 300 ml of water and stirred, followed by acetic acid. After extracting the ethyl ester, the extract is quenched with saturated brine, and then the water is removed with magnesium sulfate and filtered. The filtrate is removed by a rotary evaporator, and then purified by silica gel column chromatography with hexane as eluent. The light brown solid was compound 2-6-b (9.15 g, 21%). |
|
With copper(l) iodide; sodium butanolate; In 1,4-dioxane; at 80℃; for 6h; |
Compound 125 can be synthesized by a person of ordinary skill following Scheme 5 illustrated in FIG. 6. In the first step, compound S5-1 (available for purchase from Acros Organics, CAS No. 589-87-7) is combined with compound S5-2 (available for purchase from ArkPharm, Inc., CAS No. 6267-02-3), nBuONa and Cul in dioxane at 80 C for 6 hours to form compound S5-3. In the second step, compound S5-3 is is added to hexanes and cooled to 0 C before dropwise addition of nBuLi, followed by addition of B(OMe)3. The reaction can be allowed to stir before being quenched with aqueous HC1 to form compound S5-4. In the third step, compound S5-4 can be combined with compound S5-5 (available for purchase from Acros Organics, CAS No 626-39-1), Pd(OAc)2 and K3P04 in THF at 45 C for 24 hours to form compound S5-6. In the fourth step, compound S5-6 can be combined with compound 55- 7 (available for purchase from Acros Organics, CAS No 1692-15-5), Pd(OAc)2 and K3P04 in THF at 45 C for 24 hours to form compound 125. It is understood that steps 1, 2, 3, and 4 can be performed and optimized by a person having ordinary skill in the art without undue experimentation. |
|
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 160℃; for 24h;Inert atmosphere; |
Under a nitrogen atmosphere, <strong>[6267-02-3]9,9-dimethyl-9,10-dihydroacridine</strong> (1 g, 4.78 mmol),4-bromo-1-iodobenzene (1.75g, 6.21mmol),K2CO3 (1.32g, 9.56mmol) and Cu (1.21g, 19.1mmol) were dissolved in 12mLN, N-dimethylformamide (DMF) solution,Stir at 160 C for 24 hours. After returning to room temperature, the reaction mixture was poured into water,It was extracted with dichloromethane, and the organic layer was completely washed with brine, and then dried over anhydrous magnesium sulfate.Purification by silica gel column chromatography gave a white solid. |
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