* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With tin(II) chloride dihdyrate In ethanol for 3 h; Reflux
3-Chloro-5-methyl-phenylamine. An ethanol solution (75 mL) containing 1-chloro-3-methyl-5-nitro-benzene (5.0 g, 29 mmol) are added with SnCl2.2H2O (32.8 g, 146 mmol). The reaction mixture was reflux for 3.0 h. The solution was concentrated under vacuum, and the residue was re-dissolved in aqueous NaOH, filtered, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-chloro-5-methyl-phenylamine (4.0 g) as light yellow solids in 97percent yield: 1H NMR (500 MHz, CDCl3) δ 6.56 (s, 1H), 6.48 (s, 1H), 6.36 (s, 1H), 3.66 (bs, 2H), 2.23 (s, 3H); ESI-MS: m/z 141.7 (M+H)+.
97%
for 3 h; Reflux
An ethanol solution (75 mL) containing 1-chloro-3-methyl-5-nitro-benzene (5.0 g, 29 mmol) were mixed with SnCl2.2H2O (32.8 g, 146 mmol). The reaction mixture was refluxed for 3.0 h. The solution was concentrated under vacuum, and the residue was re-dissolved in aqueous NaOH, filtered, and extracted with EtOA.c. The organic layer was collected, washed with brine, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-chloro-5- methyl-phenylamine (4.0 g) as light yellow solids in 97percent yield: 1H NMR (500 MHz, CDCl3) δ 6.56 (s, 1 H), 6.48 (s, 1 H), 6.36 (s, 1 ), 3.66 (s, 2 H), 2.23 (s, 3 H); ESI-MS: m/z 141.7 (M + H)+.
80%
Stage #1: With tin(IV) chloride In ethanol at 4 - 20℃; for 4 h; Stage #2: With sodium hydroxide In ethanol; water at 0℃;
3-Chloro-5-nitrotoluene (45 g, 0.241 mol) and ethanol (500 ml) were mixed in a 2 litter four-neck flask. The mixture was cooled to about 4 deg C. A solution of tin chloride monohydrate (217.67 g, 0.965 mol) in 200 ml of ethanol was added dropwise to the mixture over 2 hours, while the reaction mixture was maintained at 10 deg C. or lower. Then the reaction product mixture was stirred at room temperature for 2 hours and poured into 2500 ml of iced water. It was neutralized with sodium hydroxide and filtered with a nutsche filled with sellaite. The residue was washed with ethyl acetate. The intended product was obtained with ethyl acetate from the filtrate liquid. Then the extract liquid and the washing liquid were jointed. The mixture was washed with water and then a saturated salt water and dried with magnesium sulfate. Concentrated, it was treated by distillation at a reduced pressure to obtain 28.0 g of a yellow liquid (production yield 80percent). B.p.: 85-92 deg C./0.4 kPa or lower (3 Torr or lower) 1H-NMR, 500 MHz, in CDCl3 (delta) 6.56 (bs, 1H), 6.48 (dd, JI, J2=1.3 Hz, 1H), 6.36 (bs, 1H), 3.64 (bs, 2H), 2.22 (s, 3H)
80%
Stage #1: With tin(ll) chloride In ethanol for 3 h;
Example LII; 3-chloro-5-methyl-aniline; 2.4 g of 3-chloro-5-nitro-toluene are dissolved in 35 ml of ethanol, combined with 15.8 g tin dichloride-dihydrate and refluxed for 3 hours. The solvent is eliminated in vacuo, the residue is taken up in 4 M sodium hydroxide solution and filtered through kieselguhr. The filter cake is washed thoroughly with ethyl acetate. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 81 :15 to 70:30). Yield: 1.59 g (80 percent of theory) Mass spectrum (ESI+): m/z = 142 [M+H]+
Reference：
[1] Patent: US2011/230486, 2011, A1, . Location in patent: Page/Page column 31-32
[2] Patent: WO2013/82324, 2013, A1, . Location in patent: Paragraph 00358
[3] Journal of Medicinal Chemistry, 2000, vol. 43, # 25, p. 4726 - 4737
[4] Patent: US2004/147776, 2004, A1, . Location in patent: Page 2
[5] Patent: WO2008/113760, 2008, A2, . Location in patent: Page/Page column 137
[6] Chemische Berichte, 1887, vol. 20, p. 2419
[7] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 829 - 831
[8] Chemische Berichte, 1887, vol. 20, p. 2419
[9] Patent: US5599814, 1997, A,
[10] P. Ch. S., # 154,
[11] Catalysis Science and Technology, 2016, vol. 6, # 12, p. 4473 - 4477
[12] Patent: WO2016/94260, 2016, A1, . Location in patent: Page/Page column 41
2
[ 69951-02-6 ]
[ 16582-38-0 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With sulfuric acid In ethanol at 20℃; Stage #2: With sodium nitrite In ethanol; water at 5 - 45℃;
2-Chloro-4-nitro-6-methylaniline (55.0 g, 0.295 mol) and ethanol (500 ml) were mixed in a 2 litter four-neck flask. A conc. Sulfuric acid (120 ml) was added dropwise to the reaction mixture at a temperature being lower than room temperature. The reaction mixture was maintained at a temperature of 5 to 10 deg C. and an aqueous solution of sodium nitrite (26.44 g, 0.381 mol/40 ml) was added dropwise thereto over a period of 40 minutes. The reaction mixture was then stirred at room temperature. It was observed that the temperature elevated up to 45 deg C. by way of the reaction heat and then decreases down to lower than 40 deg C. and then the reaction mixture was stirred at a temperature of 40 to 45 deg C. until no foaming. The product mixture was cooled to room temperature and poured into 2500 ml of iced water to obtain precipitates. They were filtered and dried at a reduced pressure to obtain 45.95 g of a yellow solid (production yield 90percent). 1H-NMR, 500 MHz, in CDCl3 (delta) 8.03 (bs, 1H), 7.94 (bs, 1H), 7.50 (bs, 1H), 2.46 (s, 3H)
Reference：
[1] Patent: US2004/147776, 2004, A1, . Location in patent: Page 2
[2] Chem. News J. Ind. Sci., 1895, vol. 72, p. 58[3] Chem. Zentralbl., 1895, vol. 66, # II, p. 530
[4] P. Ch. S., # 154,
3
[ 5465-33-8 ]
[ 16582-38-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 25, p. 4726 - 4737
[2] Patent: US5599814, 1997, A,
4
[ 618-85-9 ]
[ 16582-38-0 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 829 - 831
5
[ 99-52-5 ]
[ 16582-38-0 ]
Reference：
[1] Chem. News J. Ind. Sci., 1895, vol. 72, p. 58[2] Chem. Zentralbl., 1895, vol. 66, # II, p. 530
6
[ 618-61-1 ]
[ 16582-38-0 ]
Reference：
[1] Chemische Berichte, 1887, vol. 20, p. 2419
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 829 - 831
7
[ 16582-38-0 ]
[ 22233-54-1 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1969, p. 624 - 628
With tin(II) chloride dihdyrate; In ethanol; for 3.0h;Reflux;
3-Chloro-5-methyl-phenylamine. An ethanol solution (75 mL) containing <strong>[16582-38-0]1-chloro-3-methyl-5-nitro-benzene</strong> (5.0 g, 29 mmol) are added with SnCl2.2H2O (32.8 g, 146 mmol). The reaction mixture was reflux for 3.0 h. The solution was concentrated under vacuum, and the residue was re-dissolved in aqueous NaOH, filtered, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-chloro-5-methyl-phenylamine (4.0 g) as light yellow solids in 97% yield: 1H NMR (500 MHz, CDCl3) delta 6.56 (s, 1H), 6.48 (s, 1H), 6.36 (s, 1H), 3.66 (bs, 2H), 2.23 (s, 3H); ESI-MS: m/z 141.7 (M+H)+.
97%
With tin(II) chloride dihdyrate; ethanol; for 3.0h;Reflux;
An ethanol solution (75 mL) containing <strong>[16582-38-0]1-chloro-3-methyl-5-nitro-benzene</strong> (5.0 g, 29 mmol) were mixed with SnCl2.2H2O (32.8 g, 146 mmol). The reaction mixture was refluxed for 3.0 h. The solution was concentrated under vacuum, and the residue was re-dissolved in aqueous NaOH, filtered, and extracted with EtOA.c. The organic layer was collected, washed with brine, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-chloro-5- methyl-phenylamine (4.0 g) as light yellow solids in 97% yield: 1H NMR (500 MHz, CDCl3) delta 6.56 (s, 1 H), 6.48 (s, 1 H), 6.36 (s, 1 ), 3.66 (s, 2 H), 2.23 (s, 3 H); ESI-MS: m/z 141.7 (M + H)+.
80%
3-Chloro-5-nitrotoluene (45 g, 0.241 mol) and ethanol (500 ml) were mixed in a 2 litter four-neck flask. The mixture was cooled to about 4 ° C. A solution of tin chloride monohydrate (217.67 g, 0.965 mol) in 200 ml of ethanol was added dropwise to the mixture over 2 hours, while the reaction mixture was maintained at 10 ° C. or lower. Then the reaction product mixture was stirred at room temperature for 2 hours and poured into 2500 ml of iced water. It was neutralized with sodium hydroxide and filtered with a nutsche filled with sellaite. The residue was washed with ethyl acetate. The intended product was obtained with ethyl acetate from the filtrate liquid. Then the extract liquid and the washing liquid were jointed. The mixture was washed with water and then a saturated salt water and dried with magnesium sulfate. Concentrated, it was treated by distillation at a reduced pressure to obtain 28.0 g of a yellow liquid (production yield 80%). B.p.: 85-92 ° C./0.4 kPa or lower (3 Torr or lower) 1H-NMR, 500 MHz, in CDCl3 (delta) 6.56 (bs, 1H), 6.48 (dd, JI, J2=1.3 Hz, 1H), 6.36 (bs, 1H), 3.64 (bs, 2H), 2.22 (s, 3H)
80%
Example LII; 3-chloro-5-methyl-aniline; 2.4 g of <strong>[16582-38-0]3-chloro-5-nitro-toluene</strong> are dissolved in 35 ml of ethanol, combined with 15.8 g tin dichloride-dihydrate and refluxed for 3 hours. The solvent is eliminated in vacuo, the residue is taken up in 4 M sodium hydroxide solution and filtered through kieselguhr. The filter cake is washed thoroughly with ethyl acetate. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 81 :15 to 70:30). Yield: 1.59 g (80 % of theory) Mass spectrum (ESI+): m/z = 142 [M+H]+
c. 3-Chloro-5-methylaniline Using a procedure similar to that described in Example 20a except starting with <strong>[16582-38-0]3-chloro-5-nitrotoluene</strong>, the title compound was obtained (85%)as a yellow solid; MS(CI): 142 (M+H). 300-MHz 1 H NMR (DMSO-d6): 6.56 (s, 1H), 6.48 (s, 1H), 6.36 (s, 1H), 3.65 (br s, 2H), 2.22 (s, 3H).
With ethanol; tin(IV) chloride; at 85℃; for 2.0h;
To a solution of l-chloro-3-methyl-5 -nitrobenzene (1.61 g, 9.38 mmol) in EtOH (30 ml) was added tin chloride (8.90 g, 46.9 mmol). The reaction was heated at 85C for 2 h and was then quenched with INNaOH (50 mL) and extracted with EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2x). The combined organic phase was washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica (Eluant: Hexane:EtOAc = 100:0 ~ 40:60) to afford the title compound 3-chloro-5-methylaniline. LCMS calc. = 142.03; found = 141.92 (M+H)+. 1H NMR (500 MHz, CDCI3): delta 6.56 (s, 1 H); 6.49 (s, 1 H); 6.37 (s, 1 H); 3.65 (brs, 2 H); 2.23 (s, 3 H).
2-Chloro-4-nitro-6-methylaniline (55.0 g, 0.295 mol) and ethanol (500 ml) were mixed in a 2 litter four-neck flask. A conc. Sulfuric acid (120 ml) was added dropwise to the reaction mixture at a temperature being lower than room temperature. The reaction mixture was maintained at a temperature of 5 to 10 ° C. and an aqueous solution of sodium nitrite (26.44 g, 0.381 mol/40 ml) was added dropwise thereto over a period of 40 minutes. The reaction mixture was then stirred at room temperature. It was observed that the temperature elevated up to 45 ° C. by way of the reaction heat and then decreases down to lower than 40 ° C. and then the reaction mixture was stirred at a temperature of 40 to 45 ° C. until no foaming. The product mixture was cooled to room temperature and poured into 2500 ml of iced water to obtain precipitates. They were filtered and dried at a reduced pressure to obtain 45.95 g of a yellow solid (production yield 90%). 1H-NMR, 500 MHz, in CDCl3 (delta) 8.03 (bs, 1H), 7.94 (bs, 1H), 7.50 (bs, 1H), 2.46 (s, 3H)
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;
5-Chloro-3-nitrotoluene (synthesized following Journal ofMedicinal Chenaistry, 2000, 43, 4733) (0.33 g, 1.9 mmol) and NBS (0. 34 g, 1.9 mmol) were dissolved in 9 mL of CC14 and 10 mg of benzoylperoxide were added. The reaction was refluxed over night and the cooled to room temperature. The reaction mixture was filtered and the solvent evaporated after which the residue was dissolved in dichloromethane and was filtered through a plug of silica. The solvent was again evaporated to give 0.55 g crude product containing starting material the monobrominated and the dibrominated benzyl compound. Purification on silica (diethyl ether/heptane 9: 1) gave 0.13 g (27% yield) of 5-chloro-3-nitrobenzylbromide.
27%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;
5-Chloro-3-nitrotoluene (synthesized following Journal of Medicinal Chemislry, 2000, 43, 4733) (0.33g, 1. 9 mmol) and NBS (0.34 g, 1.9 mmol) were dissolved in 9 mL of CC14 and 10 mg of benzoylperoxide were added. The reaction was refluxed over night and then cooled to room temperature. The reaction mixture was filtered and the solvent evaporated after which the residue was dissolved in dichloromethane and was filtered through a plug of silica. The solvent was again evaporated to give 0.55 g crude product containing starting material the monobrominated and the dibrominated benzyl compound. Purification on silica (diethylether/heptane 9 : 1) gave 0. 13 g (27% yield) of 5-chloro-3-nitrobenzylbromide.
With sulfuric acid; sodium nitrite; In ethanol; water;
b. 3-Chloro-5-nitrotoluene To a stirred mixture of 2-chloro-4-methyl-6-nitroaniline (7.39 g, 39.7 mM) and concentrated sulfuric acid (6.2 mL) in absolute ethanol (50 mL) at 0-5 C. was slowly added a solution of sodium nitrite (6.85 g, 99.3 mM) in water (6 mL). The temperature of the reaction mixture was not allowed to exceed 5 C. during the addition. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 hr and then at reflux until the evolution of gas from the reaction mixture ceased. The reaction mixture was allowed to cool and was concentrated. The residue was slurried with ether and then filtered to remove the solids. The liltrate was concentrated and the residue chromatographed (eluant: diethyl ether/hexane; 1/9) to provide (6.25 g, 92%) the title compound as a yellow crystalline solid, mp 60.5-61 C.; MS(CI): 172 (M+H). Analysis for C7 H6 ClNO2 Calculated: C, 49.00; H, 3.52; N, 8.16 Found; C, 49.05; H, 3.53; N, 8.16
With N-Bromosuccinimide; In acetonitrile; at 80℃; for 24.0h;
Mixed 3-chloro-5-nitro-toluene (10 g), ACN (200 mL), NBS (re-crystallized, 2.5 eq), AIBN (500 mg) at room temperature then at 80C for 24 hours. Diluted with water and extracted with EtOAc (2x50 mL), dried the organic layer over NaiSCri, filtered, concentrated. Two batches of this material were purified by COMBIFLASH [1% EtOAc- hexane] to afford 5 g of 2.
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