N-(4-Aminophenyl)-N,4-dimethyl-1-piperazineacetamide

2-Chloro-N-methyl-N-(4-nitro-phenyl)-acetamide (210.0 g / 0.9185 mol) was suspended in toluene (1157.56 ml) and heated to 40°C. N-Methylpiperazine (252.65 ml / 2.48 eq) was added dropwise within 30 minutes. The reaction was stirred for 2 hours at 55°C. After cooling to ambient temperature, the reaction was washed with water (157.23 ml) and the organic layer diluted with iPrOH (1075.33 ml). Pd/C (18.81 g) was added and the reaction hydrogenated with 3/4 (lbar) at 20°C over night. After complete conversion the catalyst was filtered off, the filtrate concentrated to ~ 150 ml and triturated with EtN-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylendiamine 40 g of N-methyl-4-aminonitrobenzene and 320 ml of ethyl acetate were added to a 1-liter three-necked flask at 20 to 25 ° C over 30 minutesA mixed solution of 31.2 g (1.05 eq) of chloroacetyl chloride and 80 ml of ethyl acetate was added dropwise to the reaction solution. Dripping finished, heated to 50 ~ 55 , PaulTemperature reaction for 2 hours, TLC monitoring reaction point disappeared (the development of ethyl acetate: petroleum ether = 2: 1, Rf = 0.42), cooled to 20 ~ 25 , 40 ml of water was added to the reaction solution, stirred for 15 minutes, and the organic phase was poured into a 1-liter three-necked flask. Control the temperature at 20 ~ 25 , will be 65.80G (2.5 eq)N-methylpiperazine was added dropwise to the reaction flask, Drop finished, Heated to 45 ~ 50 , Insulation reaction for 4.5 hours, TLC monitoring reactionThe disappearance of the dross (developing solvent: dichloromethane: methanol = 2: 1, Rf = 0.61)Cooling to 10 ~ 15 , adding 120 ml of 28percent ammonia and 120 ml of water, Add 140 grams (3.0eq) of insurance powder in batches, Plus heating, heating to 50 ~ 55 , insulation reaction 2.5 hours, TLC monitoring reaction pointDisappeared (developing agent for dichloromethane: methanol = 2: 1, Rf = 0.46), cooled to 20-25 ° C, separated, 50 ml of ethyl acetate, washed with water, 50Ml saturated brine, dried over anhydrous sodium sulfate, concentrated, the residue by adding 80 ml of ethyl acetate to recrystallize, filter, filter cake 45 blastDried to give 54.67 g of a white powder in a yield of 79.27percent. Purity: 98.91percent.Into a 500 mL reaction flask, 150 mL of 1, 4-dioxane was added to 25.0 g of methyl (3-bromo-3-phenylmethylene)-2-oxoindoline-6-formate oil which was obtained by rotary evaporation from the previous reaction step, stirred until fully dissolved, 13.2 g of compound VI and 10.4 g of potassium carbonate were added, heated to 50-60 C. and reacted for 1-2 hours until TLC showed the disappearance of the raw materials. After filtered to remove the salt, the reaction solution was evaporated to dryness and replaced with 200 mL of ethyl acetate, washed with water (100 mL*3 times), and then 6.6 g of anhydrous magnesium sulfate was added for drying and 6.6 g of activated carbon was added for decolorization successively. The obtained solution was evaporated to dryness and replaced with methanol/n-heptane, crystallized to obtain 22.2 g of nintedanib, yield 81.9%. 1H NMR (400 MHz, DMSO-d6): 12.17 (s, 1H), 11.03 (s, 1H), 7.64-7.59 (t, J=7.6 Hz, 2H), 7.56-7.52 (t, J=7.6 Hz, 2H), 7.50-7.45 (d, 0.1=7.6 Hz, 1H), 7.43-7.40 (d, J=1.6 Hz, 1H), 7.21-7.17 (d J=8.3 Hz, 1H), 7.15-7.07 (m, 2H), 6.82-6.77 (m, 2H), 5.85-5.83 (d, J=8.3 Hz, 1H), 3.79 (s, 3H), 3.11-3.04 (m, 3H), 2.75-2.66 (m, 2H), 2.27-2.19 (m, 5H), 2.16-2.11 (m, 3H), 2.10 (s, 3H). Mass: 540.2 [M+H+].Into a 500 mL reaction flask, 200 mL of methanol was added to 25.0 g of methyl (3-chloro-3-phenylmethylene)-2-oxoindoline-6-formate oil which was obtained by rotary evaporation from the previous reaction step, stirred until fully dissolved, 20.9 g of compound VI and 15.5 g of diisopropylethylamine were added, heated to 50-60 C. and reacted for 10 hours until TLC showed the disappearance of the raw materials. The reaction solution was evaporated to dryness and replaced with 200 mL of ethyl acetate, washed with water (100 mL*3 times), and then 6.6 g of anhydrous magnesium sulfate was added for drying and 6.6 g of activated carbon was added for decolorization successively. The obtained solution was evaporated to dryness and replaced with methanol/n-heptane, crystallized to obtain 37.1 g of nintedanib, yield 86.1%. 1H NMR (400 MHz, DMSO-d6): 12.17 (s, 1H), 11.03 (s, 1H), 7.64-7.59 (t, J=7.6 Hz, 2H), 7.56-7.52 (t, J=7.6 Hz, 2H), 7.50-7.45 (d, J=7.6 Hz, 1H), 7.43-7.40 (d, J=1.6 Hz, 1H), 7.21-7.17 (d, J=8.3 Hz, 1H), 7.15-7.07 (m, 2H), 6.82-6.77 (m, 2H), 5.85-5.83 (d, J=8.3 Hz, 1H), 3.79 (s, 3H), 3.11-3.04 (m, 3H), 2.75-2.66 (m, 2H), 2.27-2.19 (m, 5H), 2.16-2.11 (m, 3H), 2.10 (s, 3H). Mass: 540.2 [M+H+].12 kg of a compound of formula (I) and 3-[methoxy(phenyl)methylene]-2-oxoindolin-6-formic acid methyl ester 13.4 kg. It was added to a mixed solution of 21 L of N, N-dimethylformamide and 84 L of anhydrous methanol, and heated under reflux. After 8 hours of reaction, the temperature of the reaction solution was lowered to 20 C or lower and stirred for 4 hours. The filter cake was shaken, the filter cake was washed with methanol, and dried to obtain 21.2 kg of a yellow solid with a molar yield of 91.6%. The purity by HPLC detection was 99.93%, the maximum unknown single impurity: 0.04%, and the impurity 2: 0.03% (see Figure 3 for the HPLC chart).The 2L glass reaction flask was 900 ml purged of unitz methanol, 90.0g 1 - acetyl -3 - [methoxy (phenyl) methylene] -2 - oxodihydroindole -6 - methyl formate (compound A) and 80.6g compound N - (4 - aminophenyl) - N, respectively. 4 -Dimethyl -1 18.2g - piperazine acetamide 45 - 50 C (25 - 30 C Compound 3h B), heating and 45 - 50 C temperature-2h raising to 1h 10:1 Drying, yield (3Z) -3 - {[ (4 - {methyl - [(4 - methylpiperaz -1 - yl) acetyl] amino} phenyl} amino} - (phenyl) methylene} -2 - oxo -2, 3 -dihydroindole -6 - methyl formate (compound C) 126.3g, CFC-91.37%, 99.89%.A mixture of the compound of formula V (lOg) and N-(4-aminophenyl)-N-methyl-2-(4- methylpiperazin-l-yl)acetamide (formula IV) (7.89g) in DMF (50ml) was stirred at about 65-70C for 4h. The reaction mass was cooled to about 25-30C and stirred for lh. Reaction mass was filtered and solid was washed with methanol. The solid wet cake was added in methanol and stirred at about 25-30C. Reaction mass was cooled to about 0-5C and piperidine (6.2ml) was added under stirring. The reaction mass was heated to about 25-30C and stirred for 5h. The reaction mass was cooled to about 0-5C and stirred for lh. The reaction mass was filtered and solid was washed with cold methanol to obtain crude nintedanib. Yield: 12gm; HPLC purity: 99.96%; Imp B: 0.02%.A solution of methyl (Z)-3-((4-acetamidophenyl)chloromethylene)-2-oxoindoline-5-carboxylate (10 mg, 0.03 mmol), A solution of methyl (Z)-3-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl) chloromethylene)-2-oxoindoline-5-carboxylate (138 mg, 0.29 mmol), N-(4-aminophenyl)-N- methyl-2-(4-methylpiperazin-1-yl)acetamide (88 mg, 0.34 mmol) and TEA (0.8 muL, 0.10 mmol) in EtOH (0.8 mL) was stirred under refluxed for overnight. The reaction solvent was evaporated under reduced pressure, and the residue was purified by column chromatography with dichloromethane/ethanol (50/1, v/v) to obtain the final compound 101 (154 mg, 76% yield): 1H NMR (500 MHz, CDCl3) _ 12.03 (s, 1H), 10.04 (s, 1H), 7.73 (dd, J = 8.2, 1.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8, 2 Hz, 3H), 6.84 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 1.7 Hz, 1H), 3.95 (t, J = 7.0 Hz, 2H), 3.75 (s, 3H), 3.20 (s, 2H), 3.00 (t, J = 7.0, 2H), 2.45 (bs, 6H), 2.28 (s, 3H), 0.92 (s, 9H), 0.07 (s, 6H); 13C NMR (125MHz, CDCl3) _ 171.4, 169.5, 167.4, 157.3, 142.3, 139.9, 139.3, 138.5, 130.5, 130.1, 128.4, 128.3, 127.9, 126.2, 124.3, 123.2, 122.6, 120.7, 115.7, 109.0, 98.6, 64.3, 59.6, 54.9, 53.3, 51.7.A solution of methyl (Z)-3-(chloro(4-(hydroxymethyl)phenyl)methylene)-2-oxoindoline- 5-carboxylate (17 mg, 0.05 mmol),

Molecular Weight:262.35
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:262.17936134
Monoisotopic Mass:262.17936134
Topological Polar Surface Area:52.8
Heavy Atom Count:19
Complexity:294
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes