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With iron; acetic acid In 5,5-dimethyl-1,3-cyclohexadiene at 25 - 105℃; Large scale
Example- 4: Preparation of 6-chloro 2-oxindole (iron as reductant) 3.5L acetic acid is charged with 1 kg of dimethyl ester of 2- nitrophenylmalonate, 4.5L xylene under stirring at 25-30°C. 0.573 kg iron powder is added in lots keeping the temperature at 25-30°C. Stirring is continued when temperature reaches at 45-50°C. Reaction mass is then heated to reach at 100-105 °Ctill HPLC showed cyclized monoester to be less than lpercent.Reaction mass is gradually cooled to reach at 30-35°C and 10L water is added slowly under stirring followed by addition of 6L of con HC1 keeping the temperature below 40°C. Contents are cooled to 10- 15°C and 6-choloro 2-oxindole is collected by filtration, washed with water till free from free acid. Crude weight: 0.7kg, areapercent= 96percent, assay=93percent Crude is purified from ethyl acetate. Dry weight: 0.43kg, yield=75percent areapercent=99.91percent, assay 99.82percent , sulphated ash:0.04percent
75%
Stage #1: With hydrogenchloride; water In methanol at 20 - 95℃; Large scale Stage #2: With tin In methanol at 45 - 95℃; Large scale
Example- 4: Preparation of 6-chloro 2-oxindole (Tin as reductant metal): 8.8 L methanol is charged with 1.1 kg dimethyl ester of 2- nitrophenylmalonate under stirring at ambient temperature followed by the addition of 4.8 L concentrated hydrochloric acid keeping the temperature in the range of 30-40°C. Contents are heated to reach at 75- 80°C till clear solution is obtained. Methanol is distilled off at 90-95°C reaction mass is compensated with 4Lwater and the reaction mass is maintained at 90-95 °C till HPLC showed malonate to be less than 2percent. Reaction mass is cooled to 45-50°C and 4L methanol is added followed by adding 0.975g tin in lots keeping the temperature in the range of 45- 50°C. Temperature is brought to 75-80°C by gradual heating and maintained for 2-3 hours. Methanol is distilled off at 90-95 °C with compensating the mass with (6.8L) 5N HC1 under stirring at 92-95 °C with HPLC monitoring for content of nitro phenyl acetic acid and nitro phenyl methyl acetate to be less than 1percent. Contents were cooled to 15- 20°C and product is filtered of, washed with water till free from acidity. Wt of crude =0.7kg, Areapercent = 96, HPLC assay= 86percent The crude mass is further purified from ethyl acetate. Dry weight = 0.5kg, yield 75percent, area: 98percent, HPLC assay 97.98percent, , sulphated ash 0.08percent
Reference：
[1] Patent: WO2013/93928, 2013, A1, . Location in patent: Page/Page column 49; 50
[2] Patent: WO2013/93928, 2013, A1, . Location in patent: Page/Page column 49
[3] Journal of Organic Chemistry, 2005, vol. 70, # 5, p. 1828 - 1834
[4] Synthesis, 1993, # 1, p. 51 - 53
[5] Patent: WO2012/20424, 2012, A1, . Location in patent: Page/Page column 13
[6] Patent: CN105753765, 2016, A,
[7] Patent: CN105753765, 2016, A,
With hydrogenchloride; acetic acid In water; acetic acid at 20 - 100℃; for 6h;
2 Example 2; Preparation of 4-chloro-2-nitrophenylacetic acid.
Example 2 preparation of 4-chloro-2-nitrophenylacetic acid. Dimethyl-(4-chloro-2-nitrophenyl)malonate (100gm) is mixed with acetic acid (200ml) at 20-25°C, followed by slow addition of concentrated hydrochloric acid (500ml). The reaction mixture is heated to 95-100°C, maintained at this temperature for 6 hours and cooled to 5-10 °C. Chilled water (1000ml) is then added to the reaction mixture and stirred for 30 minutes. The solid 4-chloro-2-nitrophenylacetic acid thus obtained is filtered and washed with water till the mother liquor shows a pH of 6.5-7. The product is dried at 65-70°C under vacuum.
Multi-step reaction with 2 steps
1: sodium hydroxide / ethanol / 6 h / 70 - 80 °C
2: hydrogenchloride / ethanol / 1 h / 0 - 40 °C / pH 6 - 6.5
Multi-step reaction with 2 steps
1: potassium hydroxide / ethanol / 6 h / 70 - 80 °C
2: hydrogenchloride / ethanol / 1 h / 0 - 40 °C / pH 6 - 6.5
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