| 90% |
|
In a flask 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.3 mmol) in DMF (30 rnL) was added NaH (60% in mineral oil, 0.21 g, 5.3 mmol). After stirring 5 min at room temperature the reaction mixture was added tosyl chloride (1.0 g, 5.3 mmol) and stirred 1 h at room temperature. The reaction mixture was diluted with H2O (100 mL) and filtered. The filtered solid was washed with H2O (20 mL) and dried 5 h under house vacuum at 80 0C to afford the title compound as a yellow solid (1.6 g, 90%). 1H NMR (500 MHz, DMSO-d6): delta 2.38 (s, 3H), 6.98 (d, J = 4.1 Hz, IH), 7.50 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 4.1 Hz, IH) MS (ES+): m/z 343 (M+H)+ |
| 90% |
|
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (1.0 g, 5.3 mmol) in DMF (30 mL) was added NaH (60% in mineral oil, 0.21 g, 5.3 mmol). The mixture was stirred for 5 min at room temperature and added tosyl chloride (1.0 g, 5.3 mmol). The mixture was stirred for 1 h at room temperature, diluted with H2O (100 mL), and filtered. The solid was washed with H2O (20 mL), and dried under vacuum 5 h at 80 0C to afford the title compound as a yellow solid (1.6 g, 90%). <n="47"/>[0158] 1H NMR (500 MHz, DMSO-J6): delta 2.38 (s, 3H), 6.98 (d, J = 4.1 Hz, IH), 7.50 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 4.1 Hz, IH)[0159] MS (ES+): m/z 342 (M+H)+ |
| 89% |
With dmap; triethylamine; In dichloromethane; at 20℃; for 5h;Cooling with ice; |
In the ice bath conditions,A solution of 2,4-dichloro-7H-pyrrole [2,3-d] pyrimidine 1.0 gWas dissolved in 50 mL of dichloromethane,To the above mixed solution, 1.06 g of p-toluenesulfonyl chloride was added slowly,Triethylamine 1.08 g,N, N-dimethylpyridin-4-amine, 0.019 g,The mixed solution was stirred at room temperature for 5 h,After the reaction is complete,To the above solution was poured into 150 mL, the organic phase was washed with water,Citric acid aqueous solution and brine solution were washed three times each. The organic phase was dried with anhydrous magnesium sulfate overnight, and the solvent was evaporated under reduced pressure to obtain crude product.Recrystallization from petroleum ether gave 1.6 g of pure white product.Yield 89%. |
| 89% |
With dmap; triethylamine; In dichloromethane; at 20℃; for 5h; |
1.0 g of 2,4-dichloro-7H-pyrrole [2,3-d]pyrimidine was dissolved in 50 mL of dichloromethane under ice bath. To the above mixed solution, 1.06 g of p-toluenesulfonyl chloride, 1.08 g of triethylamine, and 0.019 g of 4-dimethylaminopyridine were slowly added. The mixed solution was stirred at room temperature for 5 h. After the reaction was completed, 150 mL of dichloromethane was poured into the above solution, and the organic phase was washed three times with 100 mL of each of water, aqueous citric acid and brine; The organic phase was dried over anhydrous magnesium sulfate (MgSO4). Recrystallization from petroleum ether gave 1.6 g of white pure product. The yield was 89%. |
| 89.1% |
With dmap; triethylamine; In dichloromethane; at 20℃;Inert atmosphere; |
Compound 34 (3.0 g, 16.11 mmol) was added to a 250 mL single-mouth bottle with magnetic stirring.And dichloromethane (80 mL), stirred and dissolved, and then added p-toluenesulfonyl chloride (TsCl, 3.18 g, 16.92 mmol), triethylamine (3.24 g, 32.22 mmol)And 4-dimethylaminopyridine (DMAP, 60 mg, 0.48 mmol), plus,The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL).The organic layer was separated, the aqueous layer was extracted with dichloromethane (40 mL×2), and organic phases were combined.Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate.4.8g,The yield was 89.1%. |
| 89.1% |
With dmap; triethylamine; In dichloromethane; at 20℃; |
Compound 9a (3.0 g, 16.11 mmol) and dichloromethane (80 mL) were added to a 250 mL single-mouth flask with magnetic stirring, and the mixture was stirred and dissolved, and p-toluenesulfonyl chloride was added in sequence.(TsCl, 3.18 g, 16.92 mmol), triethylamine (3.24 g, 32.22 mmol)And DMAP (4-dimethylaminopyridine, 60mg, 0.48mmol), plus,The reaction mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL).The organic layer was separated and the aqueous layer was extracted with dichloromethane (40 mL×2).The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was passed through a silica gel column to give a white solid4.8 g, yield 89.1%. |
| 86% |
|
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.66 mmol) in DMF (5 mL) was added NaH (120 mg, 2.93 mmol, 60%) at 0 C, and the mixture was stirred at this temperature for 30 mm. Then paratoluensulfonyl chloride (608 mg, 3.19 mmol) was added to the mixture, and the resulting mixture was stirred at rt overnight. To the reaction mixture was added water (50 mL) to quench the reaction, and the resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a yellow solid (780 mg, 86 %).MS (ESI, pos. ion) m/z: 343.90 [M+H]+1H NMR (400 MHz, CDC13) (ppm): 8.13 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 4.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 4.0 Hz, 1H), 2.45 (s, 3H). |
| 85.3% |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 6h;Large scale; |
In a 50 L double-layered kettle, Compound II (2500 g, 13.3 mol, 1.0 e.q.) was added to 30 L of THF.Add NaH (797.8 g, 19.95 mol, 1.5 e.q.) in portions at 0 C, add, at 0 C,P-toluenesulfonyl chloride (3042 g, 15.96 mol, 1.2 e.q.) was added dropwise, and the temperature was controlled at 0 to 10 C.After the dropwise addition was completed, the reaction was stirred at 20 C for 6 h, and the reaction was completed by LC-MS.35 L of water was added to the reaction solution, and the mixture was thoroughly stirred, and the organic phase was washed with 30 L of saturated sodium hydrogen carbonate solution.After washing with 30 L of water, the mixture was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated.It was beaten with petroleum ether and dried to give Compound III-2 as a pale yellow solid 3881.3 g.The yield was 85.3%. |
| 84% |
|
To a solution of 2,4-dichloro-7Hpyrrolo[2,3-d]pyrimidine (4.5 g, 23.93 mmol) in DMF (140 mL) was added NaH (0.957g, 23.93 mmol). After stirring for 5 min at room temperature, 4-methylbenzene-1-sulfonyl chloride (4.56 g, 23.93 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (450 mL) and filtered. The solid was washed with water (90 mL) and dried to give the title compound 1a (7 g,84 % yield) as a white solid. LCMS: 342 [M+H]+. |
| 80% |
With sodium hydroxide; In acetone; at 0 - 20℃; for 2h; |
After 2,4-dicWoro-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 16.0 mmol) was dissolved in acetone (20.0 mL), 4- methylbenzenesulfonyl chloride (4.6 g, 23.9 mmol) was added thereto. After cooling to 0 C, 2 M sodium hydroxide solution (12.0 mL) was slowly added dropwise and then stirred at room temperature for 2 hours. The organic layer was isolated, treated with magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was isolated by column chromatography to obtain a title compound (2.9 g, yield: 80.0%). [H NMR (500MHz,CD3OD) delta 8.12(d, 2H), 7.76(d, 1H), 7.37(d, 2H), 6.68(d, 1H), 2.43(s, 3H) |
| 78% |
With sodium hydroxide; In water; acetone; at 20℃; |
General procedure: To a solution of S1a (150mg, 0.7978mmol) and p-toluenesulfonyl chloride (183mg, 0.9574) in acetone (10mL) was added 2 M aqueous NaOH (638muL, 1.2765mmol). The mixture was allowed to react overnight at room temperature. The product precipitates upon formation. The next day the solvent was evaporated and water was added. The precipitate was isolated via vacuum filtration, washed with water, and allowed to air dry yielding 2,4-dichloro-5-(p-tolylsulfonyl)pyrrolo[3,2-d]pyrimidine (S2a) as a free flowing solid (142mg, 52%). |
|
With dmap; triethylamine; In dichloromethane; at 20℃; for 1h; |
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.59 g, 8.46 mmol), p-toluenesulfonyl chloride (1.93 g, 10.1 mmol) and triethylamine (TEA) (2.35 mL, 16.9 mmol) in CH2Cl2 (15 mL), dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) was added. As soon as the DMAP was added, the suspension became clear. The solution was then stirred at room temperature for 1 h. It was washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (2.55 g). |
|
With dmap; triethylamine; In dichloromethane; at 20℃; for 20h; |
To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.67 g, 8.88 mmol), p- toluenesulfonyl chloride (1.72 g, 9.02 mmol) and triethylamine (2.50 mL, 18.0 mmol) in CH2C2 (15 mL), dimethylaminopyridine (30 mg, 0.24 mmol) was added. It was stirred at room temperature for 20 h. Water and CH2Ci2 were added. The organic phase was separated, washed with IN HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine as a solid (3.03 g). |
|
In N,N-dimethyl-formamide; at 20℃; for 2.15h; |
Example 74N-[2-( { [2-({3 -methoxy-4- [(4-methylpiperazin- 1 -yl)carbonyl]phenyl} amino)- 7H- pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)phenyl]-N-methylmethanesulfonamideExample 74A 2,4-dichIoro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine Example 1C (0.792 g, 4.21 mmol) was dissolved in N,N-dimethylformamide (15 ml) and 4-methylbenzene-l-sulfonyl chloride (0.803 g, 4.21 mmol) was added. The mixture was stirred at room temperature for 15 minutes then 4-methylbenzene-l-sulfonyl chloride (0.803 g, 4.21 mmol) was added. The mixture was stirred for 2 hours then diluted with 75 ml of ethyl acetate and washed with 50 ml of 2N aqueous HC1. The organic phase was dried over anhydrous Na2S04, filtered, and absorbed on silica gel. The crude material was purified by flash chromatography on silica gel, eluting with a 0 - 50% ethyl acetate / hexanes gradient to yield the title compound. MS ESI(+) m/z 341.7 [M+H]+ |
| 1.5 g |
With sodium hydroxide; In water; acetone; at 0 - 30℃; for 2 - 3h; |
To a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d] pyrimidine (l g, 0.005 mol) and toluene sulfonylchloride (1.3gm, 0.007) in 10 ml acetone cooled to about 0-5 C , a solution of sodium hydroxide in water (0.32gm in 4ml water) was added slowly at about 0-5 C .The temperature of the reaction mass was raised to 25-30 C and stirred for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of the reaction the reaction mass was filtered and washed with a mixture of acetone and water. The solid was dried under vacuum at about 50-55 C for about 10 hrs to afford 1.5 gm of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3- d]pyrimidine as yellow colored solid. (HPLC purity >98.0%) |
|
|
NaH (1.1 equiv) was slowly added at 0C to a 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) solution in THF. The reaction mixture was stirred at 0C for 0.5h. p-Toluensulfonyl chloride (1 equiv) was then added and it was stirred at 0C for 4h. The solvent was evaporated to dryness, and the crude product was diluted with H2O and extracted thrice with CH2Cl2. The organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the crude product for the next step. |
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