Name: 53179-13-8|5-Methyl-1-phenylpyridin-2(1H)-one|98%
Brand: Ambeed
SKU: A196927
Price: 5.0 USD
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Yield	Reaction Conditions	Operation in experiment
		A method, as defined in claim 1, wherein: said pharmaceutical substances include one or more compounds selected from the group consisting of: 5-Methyl-1-phenyl-2-(1H)pyridone 5-Methyl-1-(3-nitrophenyl-2)-(1H)pyridone 5-Methyl-1-(4'-methoxyphenyl)-2-(1H)pyridone 5-Methyl-1-p-tolyl-2-(1H)pyridone 5-Methyl-1-(3'-trifluoromethylphenyl)-2-(1H)pyridone 1-(4'Chlorophenyl)-5-Methyl-3)-(1H)pyridone 5-Methyl-1-(2'-naphthyl)-2-(1H)pyridone 5-Methyl-1-(1'naphthyl)-2-(1H)pyridone 3-Methyl-1-phenyl-2-(1H)pyridone ...
		A method of prevention and treatment, as defined in claim 1, wherein said pharmaceutical substance includes one or more compounds selected from the group consisting of: 5-Methyl-1-phenyl-2-(1H) pyridone 5-Methyl-1-(3-nitrophenyl-2)-(1H) pyridone 5-Methyl-1-(4'-methoxyphenyl)-2-(1H) pyridone 5-Methyl-1-p-tolyl-2-(1H) pyridone 5-Methyl-1-(3'-trifluoromethylphenyl)-2-(1H) pyridone 1-(4'Chlorophenyl)-5-Methyl-2)-(1H) pyridone 5-Methyl-1-(2'-naphthyl)-2-(1H) pyridone 5-Methyl-1-(1'naphthyl)-2-(1H) pyridone 3-Methyl-1-phenyl-2-(1H) pyridone ...
		Examples of the pyridone compounds which have been found or are believed to be effective in practicing the present invention include: 5-Methyl-1-phenyl-2-(1H) pyridone 5-Methyl-1-(3-nitrophenyl-2)-(1H) pyridone 5-Methyl-1-(4'-methoxyphenyl)-2-(1H) pyridone 5-Methyl-1-p-tolyl-2-(1H) pyridone 5-Methyl-1-(3'-trifluoromethylphenyl)-2-(1H) pyridone ...

		A use according to claim 5, in which said one or more 2-(1H) pyridone compounds are selected from the group consisting of: 5-Methyl-1-phenyl-2-(1H) pyridone 5-Methyl-1-(3-nitrophenyl-2)-(1H) pyridone 5-Methyl-1-(4'-methoxyphenyl)-2-(1H) pyridone 5-Methyl-1-p-tolyl-2-(1H) pyridone 5-Methyl-1-(3'-trifluoromethylphenyl)-2-(1H) pyridone 1-(4'Chlorophenyl)-5-Methyl-2-(1H) pyridone 5-Methyl-1-(2'-naphthyl)-2-(1H) pyridone 5-Methyl-1-(1'naphthyl)-2-(1H) pyridone 3-Methyl-1-phenyl-2-(1H) pyridone ...
	With pyridine; pyridine N-oxide; oxygen; copper diacetate; In dichloromethane; at 20℃; for 12h;Molecular sieve;	General procedure: [0578] A mixture of compound V-1 (4.3 g, 22 mmol), boronic acid V-2 (2.75 g, 14 mmol), pyridine (3.58 mL, 43.9 mmol), pyridine N-oxide (4.2 g, 43.9 mmol), 4 molecular sieve (300 mg) and Cu(OAc)2 (7.95 g, 43.9 mmol) in anhydrous DCM (200 mL) was degassed by purging with O2. The reaction mixture was stirred at r.t. for 12 hours. The suspension was filtered and filtrate was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with PE/EtOAc (10:1?2:1) to give compound V-3 (1.76 g, 36% yield). 1H NMR (CDCl3, 300 MHz) delta 7.48 (s, 1H), 7.26-7.23 (m, 2H), 7.01-6.98 (m, 2H), 6.54 (s, 1H), 4.14 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.45 (s, 3H), 2.27 (s, 3H).
	With pyridine; pyridine N-oxide; copper diacetate; In dichloromethane; at 20℃; for 12h;Molecular sieve;	General procedure: [0363] To a solution of X-4 (330 mg, 1.4 mmol) in DCM (30 mL), Cu(OAc)2 (800 mg, 4.4 mmol), X-5 (500 mg, 2 mmol), pyridine (1 mL), pyridine-N-oxide (400 mg, 4 mmol) and finely ground, activated 4 A molecular sieves (300 mg) were added. The mixture was stuffed at rt for 12 hrs under 02 atmosphere. The mixture was diluted with EtOAc (100 mL) and filtered, the filtrate was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (PE/EtOAc= 5/1) to give X-6 (280 mg, 50% yield) as a yellow solid. ?H NMR (CDC13, 400 MHz) (57.67 (s, 1H), 7.50-7.48 (m, 2H), 7.41-7.39 (m, 2H).

2
[ 1003-68-5 ]
[ 591-50-4 ]
[ 12775-96-1 ]
[ 53179-13-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In benzene;	EXAMPLE 1 5-Methyl-1-phenyl-2-(1H)-pyridone SPC3 A finely pulverized mixture containing 21.8g. of 5-methyl-2-(1H)-pyridone (J.V. Scudi, et al. U.S. Pat. No. 2,947,755), 30.4g. of anhydrous potassium carbonate, 0.25g. of zinc precipitated copper powder and 40 ml. of iodobenzene is stirred mechanically and refluxed for 18 hours. The mixture is cooled and treated with 150 ml. of benzene, filtered and the filtrate is decolorized with charcoal. The decolorized benzene filtrate is then evaporated to an oil which on trituration with petroleum ether and cooling gives 31.9g. (85%) of the product as a brown solid, m.p. 90-104. It is crystallized from hot water to yield a white solid melting at 102-psi.

Reference： [1]Patent: US3974281,1976,A

3
[ 53179-13-8 ]
[ 914918-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	With Lawessons reagent; In toluene; at 90℃;	l-phenyl-5-methyl-2-pyridinone (555.7 mg, 3 mmol) was reacted with Lawesson's reagent (606.7 mg, 1.5 mmol) in toluene (5 ml) at 900C. Reaction mixture was evaporated and the target compound was isolated by column chromatography (20-30% ethyl acetate- hexane) followed by crystallization from methyl-tert-butyl ether. Yield 403 mg (67%), yellow solid. The 1H NMR spectra was consistent with the structure of Compound 18

Reference： [1]Patent: WO2006/122154,2006,A2 .Location in patent: Page/Page column 64

4
[ 104-92-7 ]
[ 13466-41-6 ]
[ 53179-13-8 ]

Yield	Reaction Conditions	Operation in experiment
	pyridine; In dichloromethane; at 0 - 20℃; for 2h;	4-methylpyridin-2(1H)-one was dissolved in dichloromethane, to which pyridine in a catalytic amount was added. The temperature was controlled between 0 to 5 C.1-bromo-4-methoxybenzene was slowly dropped into this mixture and allowed to react at room temperature for 2 hours. The reaction mixture was poured into ice water, extracted twice with dichloromethane, and the organic layer was collected. The collected organic layer was washed with saturated saline solution, dried over sodium sulfate, and then concentrated to give a crude product. The crude product was subject to column chromatography to give the final product.

Reference： [1]Patent: US2008/161361,2008,A1 .Location in patent: Page/Page column 8-9

5
[ 1003-68-5 ]
[ 591-50-4 ]
[ 53179-13-8 ]

Yield	Reaction Conditions	Operation in experiment
67.9%	With copper; potassium carbonate; at 180℃; for 8h;	15.0 g of 2-hydroxy-5-methylpyridine and 50.5 g of iodobenzene, 22.4 g of anhydrous potassium carbonate and 0.23 g of copper powder were mixed and stirred, heated to 180 C for 8 h, filtered with suction, and the filtrate was concentrated under reduced pressure to give pyridine. The crude phenidone is then added to 50 mg of ethyl acetate, and dissolved by heating. The mixture is cooled to 0 C and stirred for 2 h. Then add 80ml of water, stir, heat to 80 C for 30min, add 10ml of absolute ethanol, continue heating and reflux for 1h, add activated carbon 2.0g decolorization for 30min, filter, the filtrate is cooled to 0 C for 8h, suction filtration, with absolute ethanol Washing, drying at 60 C for 8 h to obtain white crystalline pirfenidone 17.3 g, the yield of 67.9%.
56%	With potassium carbonate;copper; at 180 - 190℃; for 7h;	EXAMPLE 1 5-Methyl-1-phenylpyridin-2(1H)-one 5-Methyl-1-phenyl-1H-pyridin-2-one: A finely pulverized mixture of 2-hydroxy-5-methylpyridine (0.500 g, 4.58 mmol), anhydrous potassium carbonate (0.693 g, 6.41 mmol), copper powder (0.006 g, 0.09 mmol) and iodobenzene (1.68 g, 8.26 mmol) was heated at 180-190 C. for 7 hours. The mixture was cooled, and standard extractive workup was performed to afford a brown residue which was triturated with petroleum ether and recrystallized from hot water to yield the title compound as a white solid (0.470 g, 56%). m.p. 105-107 C.; 1H NMR (400 MHz, DMSO-d6) delta 2.50 (s, 3H), 6.43 (d, J=9.3 Hz, 1H), 7.36-7.53 (m, 7H); IR (KBr) nu 3045, 1675, 1611, 1531, 1270 cm-1; MS 186 (M+1).
56%	With potassium carbonate;copper; at 180 - 190℃; for 7h;	EXAMPLE 1; -Methyl-l-phenylpyridin-2(lH)-one; 5-Methyl- 1 -phenyl- 1 H-pyridin-2-one:; A finely pulverized mixture of 2- hydroxy-5-methylpyridine (0.500 g, 4.58 mmol), anhydrous potassium carbonate (0.693 g, 6.41 mmol), copper powder (0.006 g, 0.09 mmol) and iodobenzene (1.68 g, 8.26 mmol) was heated at 180-190 C for 7 hours. The mixture was cooled, and standard extractive workup was performed to afford a brown residue which was triturated with petroleum ether and recrystallized from hot water to yield the title compound as a white solid (0.470 g, 56%). m.p. 105-107 C; *H NMR (400 MHz, DMSO-d6) delta 2.50 (s, 3H), 6.43 (d, J = 9.3 Hz, 1H), 7.36- 7.53 (m, 7H); IR (KBr) upsilon 3045, 1675, 1611, 1531, 1270 cm"1; MS 186 (M + 1).

Reference： [1]Patent: CN109593060,2019,A .Location in patent: Paragraph 0016-0019
[2]Patent: US2008/319026,2008,A1 .Location in patent: Page/Page column 22
[3]Patent: WO2012/122165,2012,A2 .Location in patent: Page/Page column 62

6
[ 53179-13-8 ]
[ 1093951-92-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; hydrogen chloride;palladium 10% on activated carbon; In water-d2; at 160℃; for 16.5h;Sealed vessel;	Example 3. 3,6-Dideutero-5-(methyl-dV)-l-phenylpyridin-2(lH)-one (Compound 106). To a thick-walled glass pressure vessel flushed with nitrogen was added pirfenidone (100 mg, 0.540 mmol), D2O (Cambridge Isotopes, 99.9 atom% D, 1.2 mL), and a stir bar. To the stirring slurry was then added 35%w/w DCl in D2O (Aldrich, 99 atom% D, 0.135 mL, 1.64 mmol) and the solids began to partially dissolve. To the mixture was added 10% palladium on carbon (10 mg, 10%w/w of pirfenidone) and the vessel was flushed once more with nitrogen. The vessel was then flushed with hydrogen and sealed. The vessel was heated in a 160 C oil bath for 16.5 hours with stirring (this reaction time varies with reaction scale). The vessel was cooled to rt and flushed with nitrogen. The reaction mixture was diluted with CH2Cl2 (25 mL), stirred vigorously, and filtered through a 0.45 micron syringe filter. The palladium residue in the filter was flushed with CH2Cl2 (50 mL) and the combined filtrate bilayer was poured into a separatory funnel. Saturated aqueous sodium bicarbonate (50 mL) was added and the layers were shaken and separated. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to afford the title compound as a clear, colorless residue (57 mg). The residue solidified upon standing. 1H NMR (300 MHz, CDCl3) delta 7.26 (s, IH), 7.36 - 7.50 (m, 5H). 1H NMR (300 MHz, THF-d8) delta 7.20 (s, IH), 7.30 - 7.43 (m, 5H). LCMS mlz 191.0 [M + H]. This method produced batches of Compound 106 for which 1H NMR integration indicated the presence of hydrogen at the methyl group as 15% - 26% relative to the protio compound; at the R1 position as 2% - 7% relative to the protio compound; and at the R3 position as 5% - 12% relative to the protio compound.

Reference： [1]Patent: WO2009/35598,2009,A1 .Location in patent: Page/Page column 31

7
[ 53179-13-8 ]
[ 1132025-33-2 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1: 6--Deutero-5-methyl-1-phenylpyridin-2(1H)-one (Formula I, R3 is D). To a reaction vessel was added pirfenidone (25 mg, 0.135 mmol), CD3OD (Cambridge Isotopes, 99.8 atom% D, 1 mL), 40%w/w NaOD in D2O (Aldrich, 99.5 atom% D, 0.5 mL), and a stirbar. The reaction mixture was heated with vigorous stirring at 65 C for 16 h. The reaction mixture was quenched via dropwise addition of 35%w/w DCl in D2O (Aldrich, 99 atom% D, 0.75 mL). The resulting milky opaque mixture was diluted with water and the resulting clear colorless solution was transferred to a separatory funnel. The solution was extracted twice with CHCl3 (10 mL, 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield the title compound as a clear colorless residue (28 mg). 1H NMR (300 MHz, CDCl3) «5 2.10 (s, 3H), 6.67 (d, J= 9.3, IH), 7.28 (d, J= 9.3, IH), 7.36 - 7.49 (m, 5H). LCMS mlz 187.1 [M + H]. 1H NMR integration indicated the presence of hydrogen at the R3 position as 29% relative to the protio compound.

Reference： [1]Patent: WO2009/35598,2009,A1 .Location in patent: Page/Page column 29-30

8
[ 53179-13-8 ]
[ 1093951-87-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 2. 3 -Deutero-5 -methyl- l-phenylpyridin-2(lH>one (Formula I. R1 is D). To a microwave reactor vial was added pirfenidone (20 mg, 0.108 mmol), 35%w/w DCl in D2O (Aldrich, 99 atom% D, 1.25 mL), and a stirbar. The vial was sealed and the clear colorless solution was heated in a Biotage Personal Chemistry microwave reactor for 30 min at 170 0C. The vial was cooled to room temperature (rt) and the reaction mixture was transferred to a separatory funnel. The mixture was diluted with water and CH2Cl2. The acidic aqueous layer was neutralized via the careful addition of 5N aqueous NaOH. The layers were shaken and separated. The aqueous layer was extracted with CH2Cl2 and the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield the title compound as a clear colorless residue. 1H NMR (300 MHz, CDCl3) delta 2.11 (s, 3H), 7.12 (m, IH), 7.28 (m, IH), 7.36 - 7.50 (m, 5H). LCMS mlz 186.9 [M + H]. 1H NMR integration indicated the presence of hydrogen at the R1 position as 0.1% relative to the protio compound.

Reference： [1]Patent: WO2009/35598,2009,A1 .Location in patent: Page/Page column 30

9
[ 108-86-1 ]
[ 1003-68-5 ]
[ 53179-13-8 ]

Yield	Reaction Conditions	Operation in experiment
78%		5-Methylpyridin-2(1H)-one (100 Kg), potassium carbonate (127kg) and N,N-Dimethyl fonnamide (200 L) was charged in clean and dry RBF. Heat the reaction mass to 70-80C and maintain for 1 hour. Add Copper powder (4.7 Kg with particle size 75 microns) at 70-80C and maintain for another 1 hour. Add Bromobenzene (173 Kg, HPLC Purity: 99.0%) at 70-80C and heat the reaction mass to reflux (130-145C) and maintain for 12 hours for reaction completion. After completion of reaction, mass was cooled to room temperature (25-35C) and charge Dichloromethane (800 L). The mixture was filtered and washed with dichloromethane (400 L). The filtrate was washed with water (1000 L) and the washed aq.layer was extracted with dichloromethane (250 L). The combined organic layer waswashed with 20% sodium hydro sulfite solution (200 L) followed by water (200 L). The organic layer was treated with activated carbon (10 Kg) and wash with dichloromethane (100 L). The combined organic layer was distilled to get residual product to which water (500 L) was charged and acidified with aq. HC1 (100 L) to get clear solution. The mass was treated with activated carbon (10 kg) and passed through hyflo. The obtained filtrate was basifiedwith 20% NaOH solution to basic pH (10.5-11.5) at 10-15 C to crystallize the product.Cyclohexane was charged to the mass and stirred for 2-3 hours at 10-15C. Finally, theproduct was separated by filtration and dried to get Pirfenidone (5-methyl-1-phenylpyridin-2( 1H)-one). Yield: 78% HPLC Purity: >99.8%
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%.
76%	With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; for 1h;Reflux;	To a 25 mL round bottom flask was added 0.10 g (1 mmol, 1 quiv.) Of compound 3,0.17 g (1 mmol, 1 quiv.) Bromobenzene, 1.4 g (10 mmol, 10 equiv.) K2CO3,0.05 g (0.26 mmol, 0.25 equiv.) CuI,5 mL of DMF as solvent,Reflux stirring reaction 1h,TLC followed by reaction completion, cooling, adding 30 mL of water, 3 x 20 mL of ethyl acetate extraction, and an organic layer of anhydrous sulfuric acidSodium dry, spin dry, 300 mesh silica gel column chromatography, eluent petroleum ether: ethyl acetate = 1: 3 (v / v) to give pirfenidone,The yield was 76%.

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).

Reference： [1]Patent: WO2017/130166,2017,A1 .Location in patent: Page/Page column 21; 22
[2]Patent: CN105884680,2016,A .Location in patent: Paragraph 0072; 0073; 0074; 0075; 0076
[3]Patent: CN106083702,2016,A .Location in patent: Paragraph 0117; 0118; 0119; 0120; 0121
[4]Patent: CN106083817,2016,A .Location in patent: Paragraph 0090; 0091; 0092; 0093; 0094
[5]Patent: CN105998016,2016,A .Location in patent: Paragraph 0112; 0113
[6]Patent: US2018/9753,2018,A1 .Location in patent: Paragraph 0067-0068
[7]Patent: WO2010/141600,2010,A2 .Location in patent: Page/Page column 13-14
[8]Patent: WO2016/122420,2016,A1 .Location in patent: Page/Page column 6
[9]Patent: CN105315198,2016,A .Location in patent: Paragraph 0017
[10]Patent: WO2017/122139,2017,A1 .Location in patent: Page/Page column 9; 10
[11]Patent: WO2018/178996,2018,A1 .Location in patent: Page/Page column 6

10
1-Menthol [ No CAS ]
[ 53179-13-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 11 In substantially the same manner as in Example 1, except that, besides the dissolving agent, 4 parts of 1-menthol was further used as a permeation enhancer (with respect to the amount of each component, see Table 1 below), the adhesive preparation of Example 11 containing 20% of 5-methyl-1-phenyl-2-(1H)-pyridone was obtained.

Reference： [1]Patent: EP2359827,2011,A1

11
[ 1003-68-5 ]
[ 98-80-6 ]
[ 53179-13-8 ]

Reference： [1]Green Chemistry,2017,vol. 19,p. 5046 - 5053
[2]Heterocyclic Communications,2012,vol. 18,p. 193 - 197

12
[ 53179-13-8 ]
[ 1347692-68-5 ]

Yield	Reaction Conditions	Operation in experiment
61.7%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 4h;Reflux;	5-bromomethyl-1-phenylpyridine-2(1H)-one:5-methyl-1-phenylpyridine-2(1H)-one (18.5 g, 0.10 mol),N-bromosuccinimide (17.8 g, 0.10 mol),A solution of azobisisobutyronitrile (3.2 g, 0.02 mol) in carbon tetrachloride (750 mL),The mixture was stirred under gentle reflux for 4 hours under a 450 W medium pressure mercury lamp.Drop to room temperature, filter, and concentrate the filtrate under reduced pressure.Column chromatography (10% petroleum ether: 90% ethyl acetate) gave 5-bromomethyl-1-phenylpyridine-2(1H)-one (16.3 g, yield 61.7%) as pale yellow solid.

Reference： [1]Patent: CN108285431,2018,A .Location in patent: Paragraph 0085; 0087-0089
[2]Archiv der Pharmazie,2013,vol. 346,p. 654 - 666

13
[ 53179-13-8 ]
[ 1347692-33-4 ]