| 76% |
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 1h;Reflux; |
In a 25 mL round bottom flask was added 0.10 g (1 mmol,1 quiv.) Compound 3, 0.17 g (1 mmol, 1 quiv.) Bromobenzene,(10 mmol, 10 equiv.) K2CO3, 0.05 g (0.26 mmol, 0.25 equiv.) CuI, 5 mL DMF as solvent, reflux for 1 h, TLC followed by reaction,Adding 30 mL of water, 3 x 20 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate,Spin-dried, 300-mesh silica gel column chromatography, eluent petroleum ether: ethyl acetate = 1: 3 (v / v),The yield of pirfenidone was 76%. |
| 76% |
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 1h;Reflux; |
In a 25 ml round-bottom flask by adding 0.10g (1mmol, 1quiv.) compound 3,0.17g (1mmol, 1quiv.) bromobenzene, 1.4g (10mmol, 10equiv.) K 2 CO 3, 0.05g (0.26mmol, 0 . 25equiv.) CuI, 5 ml DMF as solvent, stir at reflux reaction 1h, TLC tracking, the response finishes, cooling, adding 30 ml water, 3×20 ml ethyl acetate extraction, the organic layer dried anhydrous sodium sulfate, turns on lathe does, 300 mesh silica gel column chromatography separation, eluent petroleum ether: ethyl acetate = 1:3(v/v), pirfenidone obtained, the yield is 76%. |
| 62% |
With potassium carbonate; copper(I) bromide; In butan-1-ol; at 122 - 128℃; for 24h;Inert atmosphere; |
5-Methyl-2-pyridone (250 g), potassium carbonate (380 g), bromobenzene (468 g), 250 mL of 1-butanol and copper (I) iodide (43.8 g) are placed under nitrogen atmosphere in a 2 L glass reactor equipped with a mechanical stirrer and reflux condenser. The mixture is heated to a temperature of about 122-128 C. for about 24 hours, then cooled down to about 65-70 C. Toluene (625 mL), demineralized water (875 g) and NH4OH 30%-33% (138 mL) are added, while maintaining the temperature at about 60-70 C. After about 15-20 minutes, the aqueous phase is discarded and the organic phase is washed 3 times with a solution of NaCl (12.5 g) in demineralized water (250 mL) and with NH4OH 30% to 33% (28 mL). The organic phase is then concentrated under vacuum at an internal temperature of about 50-70 C. to dryness. (0068) The residue is then triturated with isopropanol to remove all toluene still present, then dissolved in isopropanol (250 mL) at a temperature of about 65 to about 70 C. The obtained solution is cooled down to 50-55 C., heated again until complete dissolution and then cooled within about 4 hours down to -10 C. The mixture is kept at these conditions for at least 30 minutes, then the resulting solid is filtered and washed with isopropanol (125 mL), previously cooled down to about -5/-10 C. About 280 g of a wet product is obtained, which once dried in a vacuum oven at 50 C. for about 12 to 20 hours provides 263 g of pirfenidone as crystalline solid. Yield 62%. |
|
With potassium carbonate;copper(I) oxide; In N,N-dimethyl-formamide; at 125℃; for 20h; |
5-Methyl-2-pyridone (1.0 equivalents), potassium carbonate (1.2 equivalents), copper(I) oxide (0.05 equivalents), bromobenzene (1.8 equivalents, with a purity of at least 98%, preferably at least 99%, or at least 99.8%), and dimethyl formamide (2.0 volume equivalents) were charged into an inert reactor. This mixture was heated to 1250C for about 18 hours. A sample was collected and analyzed for reaction completion. If reaction completion was not satisfactory, the reaction was maintained at 1250C for an additional 2 hours. The reaction mixture was then cooled to 250C to form a slurry.[0054] The resulting slurry was filtered in a Nutsche filter in order to remove salts. The filter cake was rinsed twice with toluene. The mother liquor and process liquor were collected in Vessel (A). A sodium chloride solution (15%) was charged into the product solution. The pH was adjusted to greater than or equal to 11.5 using a 32% sodium hydroxide solution. The mixture was then agitated. After agitation was stopped, the mixture was allowed to settle for at least 30 minutes to allow the two phases to separate. The organic layer was separated and the aqueous layer was extracted with toluene. The toluene extraction was added to the organic layer. The combined organics were then washed with a 15% sodium chloride solution and agitated for at least 15 minutes. The agitation was stopped and the layers were allowed to settle for at least 30 minutes. The organic layer was separated from the aqueous layer, and then carbon treated by flowing it through Zeta Carbon filters for 2 hours at 20-250C. The carbon treated solution was then concentrated under vacuum to remove all water and much of the toluene.[0055] Heptanes were then added to the concentrated solution, and it was heated to about 8O0C. The solution was slowly cooled to about O0C over at least 7 hours. The pirfenidone precipitated out of the solution, was collected by filtration and dried, using a Nutsche filter/drier. The pirfenidone cake was washed twice with a mixture of toluene and heptanes (at O0C), then vacuum dried at a temperature of about 420C. The crude pirfenidone was formed in about 85% yield.Crystallization of Pirfenidone[0056] Pirfenidone, a 32% hydrochloride solution, and deionized water were charged in an inert reactor. The mixture was heated to about 450C, then a 32% sodium hydroxide solution was titrated into the mixture until the pH was at least 11. The temperature of the mixture was maintained at about 450C during the titration. Upon reaching the pH of at least 11, the Attorney Docket: 30481/30033 A mixture was then cooled slowly to 50C, over the course of at least 2 hours. The pirfenidone crystallized from this cooled solution and was isolated in a Nutsche filter/drier. The pirfenidone cake was washed twice with deionized water (at 50C). The pirfenidone was then vacuum dried in the filter/drier at a temperature of about 450C. The pirfenidone was also milled through a loop mill in order to reduce the particle size to less than 150 mum.[0057] The resulting pirfenidone was then analyzed and the only residual solvents observed were toluene and heptanes at about 10 to 13 ppm. No ethyl acetate or butanol was detected in the pirfenidone. The amount of bis-conjugate in the purified pirfenidone was 0.03% or less. All impurities of the purified pirfenidone were less than about 0.05%. |
| 36.3 g |
With sodium acetate; potassium carbonate; copper(I) bromide; In dimethyl sulfoxide; at 135 - 140℃;Inert atmosphere; |
5-methyl-2-pyridone (2) (20 g, 0,18 mol), K2C03 (30,4 g, 0,22 mol), NaOAc (3 g, 0,036 mol, 0,2 mol eq), CuBr (2,62 g, 0,018 mol, 0.1 mol eq) [or Cu20 (1 ,29 g, 0,05 mol eq)], Bromobenzene (4) (40,28 g, 0,26 mol, 1 ,4 mol eq) and DMSO (10 mL, 0,5 V eq) was placed in a round bottom flask under a nitrogen atmosphere. Flask was heated to 135-140C and stirred at this temperature for 6-8 h. After the completion of the reaction according to HPLC analysis, reaction medium was cooled down to about 60 C. Then, 100 mL water was added to the reaction mixture followed by 4 mL NH4OH and 100 mL toluene. The resulting mixture was stirred for 15 min and the phases were separated. Aqueous phase was extracted with 2x50 mL toluene then organic phases were combined (all extractions were carried out at about 60C). Combined organic phases were filtered over a bed of celite after treatment with charcoal. After evaporation of toluene to the dryness, 36,3 g crude pirfenidone was obtained. Crude pirfenidone purity is >99,5% (HPLC analysis, UV detector 310 nm). |
| 132.5 g |
With 1,10-Phenanthroline; potassium carbonate; copper(I) bromide; In N,N-dimethyl-formamide; at 90℃; for 2h; |
Sequentially adding to the reaction bottle 5-methyl -2 (1H)-pyridone 109 g, anhydrous potassium carbonate 165 g, cuprous bromide 0.72 g, bromophenylacetic 188.4 g, 1,10-phenan throline 0.9 g and N, N-dimethyl formamide 500 ml, the mixture is heated to 90 C about 2 hours, cooling to the end 25 C, by adding 2000 ml of water mixing, filtering, in the filter cake into the reaction bottle, by adding 5% acetic acid aqueous solution 1500 ml, the temperature is increased to 90 C, filtration, filtrate with 20% sodium hydroxide solution to adjust the pH= 13, and then cooled to the 5 C the following filtering, decompression drying to obtain the pirfenidone 132.5 g, spare. |
| 120 g |
With potassium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 130 - 140℃; for 10h; |
A mixture of 5 -methyl- lH-pyridin-2-one (100 g), bromo benzene (259 g, comprising greater than 0.2% by weight dibromobenzene isomers) and dimethylformamide (200 ml) were added in to a round bottom flask and stirred up to complete dissolution. Potassium carbonate (254 g) and copper (I) chloride (18.2 g) was added to the above reaction mass and then heated to 130-140C. The reaction mass was stirred at 130-140C for 10 hrs. After the reaction completion, the reaction mass was cooled to 25-35C. Toluene (500 ml), aqueous sodium chloride (75 g of sodium chloride in 500 ml of water) was added to the reaction mass and stirred for 15-30 mins at 25-35C. The reaction mass was filtered and the filtrate was allowed to settle. Organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Organic layers combined and was washed with aqueous sodium chloride, treated with carbon and filtered through hyflo. The solvent from the filtrate was distilled off completely under vacuum at below 60C. Toluene (300 ml) was added to the obtained residue and stirred for 30 mins. The reaction mass was heated to 77-83C and stirred for 45 mins. The reaction mass was cooled to 25-35C over 60 mins. The reaction mass was further cooled to 0-6C. The solid obtained was filtered, washed with toluene and dried under vacuum. DM water (500 ml) was added to the above obtained wet compound followed by 50% aqueous sodium hydroxide solution (10 g of sodium hydroxide in 20 ml of water) at 25-35C. The reaction mass was heated to 75-85C and stirred for 30-60 mins. The reaction mass was then gradually cooled to 25-35C and stirred for 60 mins. The reaction mass was further cooled to 0-5 C and stirred for 3 hrs. The obtained solid was filtered, washed with water and dried to provide the title compound.Yield: 120 g; purity by HPLC: 99%; The XRPD is set forth in Figure 1 The DSC is set forth in Figure 2. |
|
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 25 - 130℃; |
The 5-methyl-2(lH)-pyridinone (70.0 g) was added to Dimethylformamide (70.0 mL) at 25-30C. To this reaction mixture added the Potassium carbonate (106.3 g), activated copper powder (2.04 g) and Bromobenzene (151.0 g) at 25-30C and stir for 5-10 mits. The reaction mixture heated to 125-130C for 22.0-24.0 hours. The reaction mixture cool to 25-30C and filter the salts. The salts were leached with toluene at 55-60C and filtered. Added the 15% sodium chloride solution to filtrate and adjust the pH to > 12.0 with 32% aq. Sodium hydroxide. The layers are separated and added Toluene (280.0 mL) to aqueous layer. The reaction mixture was heated to 55-60C and separate the Toluene layer. The toluene layer was dried with 15%) NaCl solution and separate the organic layer. (0036) The organic layer was treated with activated carbon at 25-30C and filtered. The filtrate was distil out completely under vacuum at < 60C and added the toluene (35.0 mL) and n-Heptane (245.0 mL) solvent mixture. The reaction mixture was heated to 75-80C and stir for 1 hour. The reaction mixture was cool to 25-30C and stir for 45-60 min. Filter the compound and wash with solvent mixture of n- Heptane (63.0 mL) and Toluene (7.0 mL). |
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