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USD 0.00
Limited Quantity
USD 15-60
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USD 80+
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Structure of 570-24-1 * Storage: {[proInfo.prStorage]}
* 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 sodium hydroxide In ethanol; water at 70℃; for 2 h; Green chemistry
General procedure: TUD (20 mmol) was added in batches to a solution of substituted 2‑nitroanilines (5 mmol) and NaOH (20 mmol) in H2O (15 mL) and EtOH (5 mL) at 70 °C. The reaction mixture was stirred for a certain period of time as required to complete the reaction (monitored byTLC). After cooling, 10percent NaOH solutions were added until pH = 9–10, the precipitated solid was filtered off and washed with water to obtain crude product. The crude product was recrystallised from water to give a white solid. The physical and spectra data of the compounds 2a–h were as follows.
Reference：
[1] Journal of Chemical Research, 2014, vol. 38, # 2, p. 118 - 120
2
[ 570-24-1 ]
[ 4887-83-6 ]
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1083
3
[ 570-24-1 ]
[ 21443-96-9 ]
Reference：
[1] Synlett, 2007, # 8, p. 1203 - 1206
[2] Chemische Berichte, 1904, vol. 37, p. 2583
[3] Archives of Pharmacal Research, 2018, vol. 41, # 1, p. 46 - 56
4
[ 570-24-1 ]
[ 2942-42-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
With acetic acid; sodium nitrite In water
To a stirred solution of step-a-c product (10 g, 0.065 mol) in acetic acid (470 ml, 47 times), a solution of sodium nitrite (1.54 g, 0.06 mol, 1.1 eq) in water (9 ml) was added and the reaction mass was stirred for 30 - 45 min. Progress of the reaction was monitored by TLC (30percent ethyl acetate/hexane, Rr-0.7). On completion of the reaction, acetic acid was distilled off and the residue obtained was taken in ice water (200 ml). Solid formed was filtered, washed with cold water and dried to yield the required product as an yellow colored solid (10 g, 98percent yield).
97%
With acetic acid; sodium nitrite In water at 20℃; for 0.333333 h; Inert atmosphere
To a solution of 2-methyl-6-nitroaniline (5.00 g, 32.80 mmol) in acetic acid (250 mL)was added a solution of sodium nitrite (2.50 g,36.10 mmol) in water (5 mL). The mixture was stirred for20 min at room temperature. Yellow precipitate formedduring reaction which was filtered and discarded. Thecombined solution was evaporated under reduced pressureand cold water was added to the residue. Pale yellow solidwas formed, filtered, rinsed with cold water and driedunder vacuum to afford 7-nitro-1H-indaozle. Yield = 97percent(5.22 g); 1H-NMR (CDCl3, 300 MHz) δ 11.4 (1H, br, NH),8.40 (1H, d, J = 9.0 Hz, Ar), 8.31 (1H, s, Ar), 8.19 (1H, d,J = 6.0 Hz, Ar), 7.37 (1H, dd, J = 6.0 Hz andJ = 9.0 Hz).
Reference：
[1] Synlett, 2007, # 8, p. 1203 - 1206
[2] Patent: WO2010/127855, 2010, A1, . Location in patent: Page/Page column 124; 125
[3] Archives of Pharmacal Research, 2018, vol. 41, # 1, p. 46 - 56
[4] European Journal of Medicinal Chemistry, 1986, vol. 21, # 4, p. 359 - 362
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2000, vol. 39, # 5, p. 339 - 345
5
[ 570-24-1 ]
[ 2942-42-9 ]
Reference：
[1] Chemische Berichte, 1904, vol. 37, p. 2583
6
[ 570-24-1 ]
[ 74209-34-0 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2000, vol. 39, # 5, p. 339 - 345
7
[ 570-24-1 ]
[ 13708-12-8 ]
Reference：
[1] Organic Process Research and Development, 2003, vol. 7, # 3, p. 318 - 323
8
[ 570-24-1 ]
[ 3970-40-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 456
[2] Journal of the Chemical Society, 1901, vol. 79, p. 1128[3] Journal of the Chemical Society, 1902, vol. 81, p. 1327,1347
[4] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1976, vol. 30, p. 141 - 149
[5] P. Ch. S., p. 154
[6] Patent: CN106187883, 2016, A, . Location in patent: Paragraph 0095; 0096
9
[ 570-24-1 ]
[ 2255-80-3 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 15, p. 6004 - 6017
10
[ 570-24-1 ]
[ 140-89-6 ]
[ 27231-33-0 ]
Reference：
[1] Patent: US5945425, 1999, A,
[2] Patent: US4687775, 1987, A,
11
[ 570-24-1 ]
[ 2687-25-4 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogen In ethanol at 20℃; for 4 h;
4.0 g of 10 percent palladium-carbon catalyst (water content, 51.5 percent) was added to ethanol (200 ml) solution of 8.50 g (55.9 mmol) of 2-methyl-6-nitroaniline, and the resulting mixture was stirred under atmospheric pressure hydrogen at room temperature for 4 hours. The catalyst was removed through filtration, and the solvent was evaporated from the filtrate to obtain 6.64 g (97 percent) of a crude product of the entitled compound as a black crystal. This compound was directly used in the next reaction.1H-NMR(CDCl3)δ: 2.22(3H, s), 3.35-3.40(4H, m), 6.62-6.68(3H, m).
85.8%
for 1 h; Reflux
o-Diamines 5a and 5b were obtained following a standard reduction procedure [28]. Twenty-seven milliliters of concentrated HCl were added gradually, through a condenser, to a mixture of 10g (0.066mol) of 4-methyl-2-nitroaniline (4a) or 2-methyl-6-nitroaniline (4b) and 12g (0.1mol) of granulated Sn. During the addition of the acid the reaction mixture was vigorously stirred. After that, the reaction mixture was refluxed for 1h, cooled to room temperature and made alkaline with a solution of 20g of NaOH in 33mL of water. (0008) The reduction product of compound 4b, 3-methylbenzene-1,2-diamine (5b), was isolated from the reaction mixture by steam distillation. Compound 5b was “salted out” by saturating the distillate with NaCl and extracted with Et2O. Combined ethereal layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. Since it was impossible to separate 4-methylbenzene-1,2-diamine (5a) by steam distillation, this diamine was directly “salted out” from the reaction mixture and extracted with Et2O. After the evaporation of the solvent, the crude 5a was purified by sublimation. The yield was 83.5percent (6.72g) and 85.8percent (6.92g) for compound 5a and 5b, respectively.
70%
Stage #1: With tin(ll) chloride In ethyl acetate for 6 h; Reflux Stage #2: With water; sodium hydrogencarbonate In ethyl acetateCooling
To a stirred solution of 2-methyl-6-nitroaniline (0.3 g, 1.97 mmol) in ethyl acetate (10 mL), 1.7 g (11.84 mmol) of stannous chloride was added and the mixture was refluxed for 6 h. The reaction was cooled and added into ice water. The ethyl acetate layer was collected and repeatedly washed with sodium bicarbonate solution. The organic layer was concentrated under vacuum and the product was obtained as orange solid (0.17 g, 70percent). m.p. 52-55° C. 1H NMR (400 MHz, CDCl3, TMS) δ 6.64 (s, 3H), 3.4 (s, 4H), 2.20 (s, 3H).
Reference：
[1] Patent: EP1479681, 2004, A1, . Location in patent: Page 110
[2] Polyhedron, 2016, vol. 105, p. 137 - 149
[3] Patent: US2012/130078, 2012, A1, . Location in patent: Page/Page column 6
[4] Heterocycles, 1997, vol. 45, # 5, p. 955 - 962
[5] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 543 - 548
[6] Justus Liebigs Annalen der Chemie, 1885, vol. 228, p. 243
[7] Chemische Berichte, 1919, vol. 52, p. 1083
[8] Journal of the Chemical Society, 1928, p. 355
[9] Tetrahedron, 1995, vol. 51, # 42, p. 11515 - 11530
[10] Journal of Organic Chemistry, 2005, vol. 70, # 15, p. 6004 - 6017
[11] Patent: US5273975, 1993, A,
[12] Patent: US4714764, 1987, A,
[13] Patent: US2007/10542, 2007, A1, . Location in patent: Page/Page column 77
[14] Patent: EP2653505, 2013, A1, . Location in patent: Paragraph 0179
[15] Organic Process Research and Development, 2003, vol. 7, # 3, p. 318 - 323
[16] Journal of Organic Chemistry, 2014, vol. 79, # 23, p. 11440 - 11453
[17] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6289 - 6304
12
[ 570-24-1 ]
[ 10034-85-2 ]
[ 2687-25-4 ]
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1083
13
[ 570-24-1 ]
[ 69190-56-3 ]
Reference：
[1] Journal of the Chemical Society, 1904, vol. 85, p. 1269
14
[ 120-66-1 ]
[ 570-24-1 ]
Yield
Reaction Conditions
Operation in experiment
39.78 g
Stage #1: With nitric acid In acetic anhydride at 10 - 12℃; for 2.5 h; Stage #2: With sulfuric acid In water for 3 h; Reflux
A slightly modified procedure of Howard was applied [27]. Toluidine (1a or 1b; 53.5mL, 0.5mol) was introduced, in small portions and under constant stirring, to Ac2O (325mL). The obtained solution was cooled to 12–13°C in an ice-salt bath. After that, under stirring and at a rate which maintained the temperature within the limits of 10–12°C, 70percent HNO3 (63mL) was added dropwise to the reaction mixture. The addition was completed in 2.5h and the solution was poured, with stirring, into 1.5L of ice-water. The precipitate (cream-colored solid) of acetamide (3a, or mixture of 3b and 3c) was collected on a Büchner funnel, washed with four 250-mL portions of ice-water and partially dried by suction. The moist acetamide (3a, or mixture of 3b and 3c) was mixed with 70percent H2SO4 (100mL) and stirred at reflux for 3h. The hydrolysis product of acetamide 3b, 2-methyl-6-nitroaniline (4b), was isolated from the reaction mixture by steam distillation. The bright orange needles of 4b, which separated when the distillate was cooled, were collected on a Büchner funnel and dried in a vacuum desiccator. In the case of the hydrolysis of acetamide 3a, the warm reaction mixture was diluted with 350mL of water and made alkaline with 10percent aq. NaOH. After cooling to room temperature 4-methyl-2-nitroaniline (4a) precipitated as a brown powder that was separated by vacuum filtration, washed with three 200-mL portions of water, and dried in a vacuum desiccator. The yield was 53.6percent (40.73g) and 52.3percent (39.78g) for compounds 4a and 4b, respectively.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1969, vol. 78, p. 571 - 582
[2] Chemistry Letters, 1989, p. 1849 - 1852
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 13, p. 6047 - 6060
[4] Polyhedron, 2016, vol. 105, p. 137 - 149
Reference：
[1] Tetrahedron Asymmetry, 2003, vol. 14, # 10, p. 1267 - 1273
[2] Chemische Berichte, 1900, vol. 33, p. 2505
[3] Journal of the Chemical Society, 1901, vol. 79, p. 1128[4] Journal of the Chemical Society, 1902, vol. 81, p. 1327,1347
[5] Journal of the Chemical Society, 1923, vol. 123, p. 3238
[6] Journal fuer Praktische Chemie (Leipzig), 1921, vol. <2>102, p. 184
[7] Chemische Berichte, 1900, vol. 33, p. 2505
[8] Journal of the Chemical Society, 1901, vol. 79, p. 1128[9] Journal of the Chemical Society, 1902, vol. 81, p. 1327,1347
20
[ 99-08-1 ]
[ 570-24-1 ]
[ 99-52-5 ]
[ 89-62-3 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 9, p. 2934 - 2935
21
[ 95-53-4 ]
[ 570-24-1 ]
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1174
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 13, p. 6047 - 6060
22
[ 120-66-1 ]
[ 570-24-1 ]
[ 2719-15-5 ]
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1083
[2] Chemische Berichte, 1919, vol. 52, p. 1174
23
[ 602-01-7 ]
[ 570-24-1 ]
Reference：
[1] Journal of the Chemical Society, 1920, vol. 117, p. 856
24
[ 3299-62-5 ]
[ 570-24-1 ]
Reference：
[1] Journal of the Chemical Society, 1921, vol. 119, p. 599
[2] Proceedings of the Chemical Society, London, 1914, vol. 30, p. 253
25
[ 591-09-3 ]
[ 120-66-1 ]
[ 570-24-1 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1929, vol. 38, p. 372
26
[ 602-01-7 ]
[ 7664-41-7 ]
[ 570-24-1 ]
Reference：
[1] Journal of the Chemical Society, 1920, vol. 117, p. 856
Reference：
[1] Bulletin des Societes Chimiques Belges, 1969, vol. 78, p. 571 - 582
34
[ 570-24-1 ]
[ 54879-20-8 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
[2] Journal of Organic Chemistry, 1976, vol. 41, # 21, p. 3356 - 3359
[3] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
35
[ 570-24-1 ]
[ 56043-01-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 6, p. 643 - 659
36
[ 570-24-1 ]
[ 22061-78-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
37
[ 570-24-1 ]
[ 41085-43-2 ]
Yield
Reaction Conditions
Operation in experiment
60%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 1 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 20℃; for 0.5 h;
General procedure: The suspension of 39 (30.4 g, 0.2 mol) in water (250 mL) and HBr (100 mL, 40percent aq) was refluxed for 10 min and then was cooled to 0 °C. A solution of NaNO2 (13.8 g, 0.2 mol) in water (80 ml) was added dropwise at <5 °C. The dizaonium solution was stirred for a further 30 min at 0-5 °C and then added slowly to a stirring mixture of CuBr (28.7 g, 0.2 mol) in HBr (80 mL) and water (150 mL) at rt. The mixture was stirred at rt for 30 min and then on a steam-bath for 1 h. The mixture was washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography with petroleum ether as eluent to give 40 as a pale yellow solid (25.9 g, yield 60percent). The mixture of 40 (14.3 g, 0.066 mol), NBS (17.7 g, 0.099 mol) and AIBN (0.3 g, 1.8 mmol) in CCl4 (250 ml) was refluxed overnight. The mixture was filtered and the filtrate was concentrated to give 41 as a red liquid (21 g). The mixture of 41 (21 g) and NaOAc (16.4 g, 0.2 mol) in DMF (300 mL) was stirred at 70 °C overnight, and then diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na3SO4 and concentrated under vacuum. The residue was purified by column chromatography with PE/EA (20:1, v/v) as eluent to give 42 as a white solid (7.7 g, 42percent over two steps). To the solution of 42 (16.5 g, 0.06 mol) in 1,4-dioxane (250 mL) was bubbled with nitrogen for 20 min. Potassium acetate (20.6 g, 0.21 mol), Pd (dppf)Cl2 (3.92 g, 4.8 mmol) and bis(pinacolato)diboron (22.9 g, 0.09 mol) were added and the reaction mixture was stirred under N2 at 95 °C for 20 h. The reaction mixture was then cooled and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography with PE/EA (20:1, v/v) as eluent to give 43 as a yellow oil (9.9 g, 51percent). MS: m/z = 322 (M+1, ESI+). To the solution of 43 (9.9 g, 0.03 mol) in methanol (300 mL) was added NaOH (5 N, 12 mL, 0.06 mol). The reaction mixture was stirred and refluxed under nitrogen for 24 h. It was then concentrated under vacuum and the residue was dissolved in THF (100 mL). HCl (5 N, 60 mL, 0.3 mol) was added and the reaction mixture was stirred and heated at 40 °C for 16 h. It was cooled, diluted with EtOAc and poured into brine. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was recrystallized from the mixed solvents of EA and PE to give 44 as a yellow solid (3.8 g, yield 71percent). 1H NMR (300 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.01 (d, 1H), 7.81 (m, 2H), 5.05 (s, 2H) ppm. MS: m/z = 180 (M+1, ESI+). To the solution of 44 (0.92 g, 5.1 mmol) in MeOH (50 mL) was added Pd/C (0.5 g) and the hydrogenation was conducted at one atmosphere and rt for 2.5 h to provide the desired product 45 as a solid (0.68 g, yield 88percent). 1H NMR (300 MHz, DMSO-d6): δ 8.78 (s, 1H), 7.10 (t, 1H), 6.47 (d, 1H), 6.39 (d, 1H), 5.32(s, 2H), 4.82(s, 2H) ppm. MS: m/z = 150 (M+1, ESI+). To a mixture of 45 (800 mg, 5.37 mmol) and K2CO3 (2.23 g, 0.0161 mol) in N,N-dimethylacetamide (17.9 mL) was added ethyl bromoacetate (0.623 mg, 3.76 mmol). The reaction was stirred overnight at rt. It was diluted with water and extracted with EA. The organic layer was washed with 2 N HCl, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography eluted with EA/DCM (10percent) to give the desired product 46 as a solid (380 mg, yield 30percent). 1H NMR (300 MHz, DMSO-d6): δ 8.98 (s, 1H), 7.20 (t, 1H), 6.60 (d, 1H), 6.25 (d, 1H), 5.63 (s, 1H), 4.86 (s, 2H), 4.14 (q, 2H), 3.80 (s, 2H), 1.20 (t, 3H) ppm. The mixture of 46 (30 mg, 0.127 mmol) and LiOH.bul.H2O(10.7 mg, 0.255 mmol) in THF/MeOH/H2O = 3:2:1 (0.51 mL) was stirred for 2 h. The mixture was purified by preparative TLC (EA/PE = 1:1) to give the desired final compound 5 as a solid (11 mg, yield 42.3percent).
60%
Stage #1: With hydrogen bromide In water for 0.166667 h; Reflux Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.5 h; Stage #3: With copper(I) bromide In water at 20 - 100℃; for 1.5 h;
2-Methyl-6-nitrobenzenamine (30.4g, 0.2mol) was suspended in water (250ml) and HBr (100ml, 40percent aq.), and the mixture was heated to reflux for 10 min. Then the mixture was cooled to O0C and NaNO2 (13.8g, 0.2mol) in water (80ml) was added dropwise at such a rate that the temperature did not exceed 50C. The dizaonium solution was stirred for a further 30 min at 0-50C and then added slowly to a stirred mixture of CuBr (28.7g, 0.2mol) in HBr (80ml) and water (150ml) at roomtemperature. The mixture was stirred at room temperature for 30 min and then on a steam-bath for Ih. The mixture was washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography with petroleum ether as eluent to give a pale yellow solid (25.9g, yield 60percent).
60%
Stage #1: With hydrogen bromide In water for 0.166667 h; Reflux Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.5 h; Stage #3: With copper(I) bromide In water at 20℃; for 1.5 h; Heating
The suspension of 2-methyl-6-nitroaniline (30.4 g, 0.2 mol) in water (250 mL) and HBr (100 mL, 40percent aq.) was refluxed for 10 min and then was cooled to 0 °C. A solution of NaNO2 (13.8 g, 0.2 mol) in water (80 mL) was added dropwise at < 5 °C. The diazonium solution was stirred for a further 30 min at 0-5 °C and then added slowly to a stirring mixture of CuBr (28.7 g, 0.2 mol) in HBr (80 mL) and water (150 mL) at room temperature. The mixture was stirred at room temperature for 30 min and then on a steam-bath for 1h. The mixture was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether as eluent to give 2-bromo-1-methyl-3-nitrobenzene as a pale yellow solid (25.9 g, yield 60percent). The mixture of 2-bromo-1-methyl-3-nitrobenzene (14.3 g, 0.066 mol), NBS (17.7g, 0.099 mol) and AIBN (0.3 g, 1.8 mmol) in CCl4 (250 mL) was refluxed overnight. The mixture was filtered and the filtrate was concentrated to give 2-bromo-1-(bromomethyl)-3-nitrobenzene as a red liquid (21 g). The mixture of 2-bromo-1-(bromomethyl)-3-nitrobenzene (21 g) and NaOAc (16.4 g, 0.2 mol) in DMF (300 mL) was stirred at 70 °C overnight, and then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether/ethyl acetate (20/1, v/v) as eluent to give 2-bromo-3-nitrobenzyl acetate as a white solid (7.7 g, 42percent over two steps).To a solution of 2-bromo-3-nitrobenzyl acetate (16.5 g, 0.06 mol) in 1,4-dioxane (250 mL) was bubbled with nitrogen for 20 min. Potassium acetate (20.6 g, 0.21 mol), Pd(dppf)Cl2 (3.92 g, 4.8 mmol) and bis(pinacolato)diboron (22.9 g, 0.09 mol) were added and the reaction mixture was stirred under N2 at 95 °C for 20 h. The reaction mixture was then cooled and concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether/ethyl acetate (20/1, v/v) as eluent to give 3-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate as a yellow oil (9.9 g, 51percent). LC-MS (ESI) m/z 322 [M+1]+, (calcd MS 321.1).To a solution of 3-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (9.9 g, 0.03 mol) in methanol (300 mL) was added NaOH (5 N, 12 mL, 0.06 mol). The reaction mixture was stirred and refluxed under nitrogen for 24 h. It was then concentrated under vacuum and the residue was dissolved in THF (100 mL). HCl (5 N, 60 mL, 0.3 mol) was added and the reaction mixture was stirred and heated at 40°C for 16 h. It was cooled, diluted with EtOAc and poured into brine. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from the mixed solvents of ethyl acetate and petroleum ether to give 7-nitrobenzo[c][1,2]oxaborol-1(3H)-ol as a yellow solid (3.8 g, yield 71percent). LC-MS (ESI) m/z 180 [M+1]+, (calcd MS 179.0). 1H NMR (300 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.01 (d, 1H), 7.81 (m, 2H), 5.05 (s, 2H).To a solution of 7-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (0.92 g, 5.1 mmol) in MeOH (50 mL) was added Pd/C (0.5 g) and the hydrogenation was conducted at one atmosphere and room temperature for 2.5 h to provide the desired product 2e as a solid (0.68 g, yield 88percent). LC-MS (ESI) m/z 150 [M+1]+, (calcd MS 149.1). 1H NMR (300 MHz, DMSO-d6): δ 8.78 (s, 1H), 7.10 (t, 1H), 6.47 (d, 1H), 6.39 (d, 1H), 5.32(s, 2H), 4.82(s, 2H).
Reference：
[1] European Journal of Organic Chemistry, 2005, # 16, p. 3536 - 3541
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
[3] Angewandte Chemie - International Edition, 2010, vol. 49, # 40, p. 7257 - 7260
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 644 - 651
[5] Patent: WO2011/22337, 2011, A1, . Location in patent: Page/Page column 97
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2048 - 2054
[7] Journal of the Chemical Society, 1952, p. 3187,3188
[8] Journal of the American Chemical Society, 1930, vol. 52, p. 5263,5264
[9] Journal of the Chemical Society, 1929, p. 1255
[10] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1976, vol. 30, p. 141 - 149
[11] Journal of Organic Chemistry, 1976, vol. 41, # 21, p. 3356 - 3359
[12] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
[13] Patent: US4329518, 1982, A,
[14] Patent: US4339457, 1982, A,
[15] Patent: US4402973, 1983, A,
38
[ 570-24-1 ]
[ 29027-17-6 ]
Reference：
[1] P. Ch. S., p. 154
[2] Patent: CN106187883, 2016, A,
39
[ 570-24-1 ]
[ 5398-69-6 ]
Reference：
[1] Journal of the Chemical Society, 1920, vol. 117, p. 775
40
[ 570-24-1 ]
[ 5337-09-7 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
41
[ 570-24-1 ]
[ 6277-17-4 ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium iodide; sulfuric acid; sodium nitrite In ice-water; ethanol; dichloromethane
PREPARATION EXAMPLE 3 Synthesis of 2-Iodo-3-nitrotoluene (6) In a 500 ml three-necked flask was charged 110 g (0.72 mole) of 2-amino-3-nitrotoluene (5) as obtained in Preparation Example 2, and 260 ml of concentrated sulfuric acid was added thereto, followed by stirring at 0° C. To the solution was added 74.8 g (1.08 mole) of sodium nitrite over 45 minutes, and the solution was stirred at 0° C. for 4 hours, whereby the solution became a dark brown suspension. The reaction mixture was poured into 3 l of ice-water, and 1 l of an aqueous 53percent potassium iodide was added thereto. After stirring at 80° C. for 10 hours, the reaction mixture was treated with 100 g of sodium hydrogensulfite. A supernatant was removed, and insoluble matters were extracted thrice with 500 ml of dichloromethane. An organic layer was neutralized and washed with a saturated sodium hydrogencarbonate aqueous solution, washed with distilled water, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain a yellowish brown crude crystal. Recrystallization of the crude crystal from 150 ml of 99percent ethanol gave 2-iodo-3-nitrotoluene (6) as a pale yellow crystal having a melting point of 64.8° to 65.2° C. and an 84percent yield (inclusive of secondary crystals recovered from the filtrate after recrystallization).
Reference：
[1] Patent: US5021593, 1991, A,
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General procedure: The suspension of 39 (30.4 g, 0.2 mol) in water (250 mL) and HBr (100 mL, 40% aq) was refluxed for 10 min and then was cooled to 0 C. A solution of NaNO2 (13.8 g, 0.2 mol) in water (80 ml) was added dropwise at <5 C. The dizaonium solution was stirred for a further 30 min at 0-5 C and then added slowly to a stirring mixture of CuBr (28.7 g, 0.2 mol) in HBr (80 mL) and water (150 mL) at rt. The mixture was stirred at rt for 30 min and then on a steam-bath for 1 h. The mixture was washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography with petroleum ether as eluent to give 40 as a pale yellow solid (25.9 g, yield 60%). The mixture of 40 (14.3 g, 0.066 mol), NBS (17.7 g, 0.099 mol) and AIBN (0.3 g, 1.8 mmol) in CCl4 (250 ml) was refluxed overnight. The mixture was filtered and the filtrate was concentrated to give 41 as a red liquid (21 g). The mixture of 41 (21 g) and NaOAc (16.4 g, 0.2 mol) in DMF (300 mL) was stirred at 70 C overnight, and then diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na3SO4 and concentrated under vacuum. The residue was purified by column chromatography with PE/EA (20:1, v/v) as eluent to give 42 as a white solid (7.7 g, 42% over two steps). To the solution of 42 (16.5 g, 0.06 mol) in 1,4-dioxane (250 mL) was bubbled with nitrogen for 20 min. Potassium acetate (20.6 g, 0.21 mol), Pd (dppf)Cl2 (3.92 g, 4.8 mmol) and bis(pinacolato)diboron (22.9 g, 0.09 mol) were added and the reaction mixture was stirred under N2 at 95 C for 20 h. The reaction mixture was then cooled and evaporated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography with PE/EA (20:1, v/v) as eluent to give 43 as a yellow oil (9.9 g, 51%). MS: m/z = 322 (M+1, ESI+). To the solution of 43 (9.9 g, 0.03 mol) in methanol (300 mL) was added NaOH (5 N, 12 mL, 0.06 mol). The reaction mixture was stirred and refluxed under nitrogen for 24 h. It was then concentrated under vacuum and the residue was dissolved in THF (100 mL). HCl (5 N, 60 mL, 0.3 mol) was added and the reaction mixture was stirred and heated at 40 C for 16 h. It was cooled, diluted with EtOAc and poured into brine. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was recrystallized from the mixed solvents of EA and PE to give 44 as a yellow solid (3.8 g, yield 71%). 1H NMR (300 MHz, DMSO-d6): delta 8.99 (s, 1H), 8.01 (d, 1H), 7.81 (m, 2H), 5.05 (s, 2H) ppm. MS: m/z = 180 (M+1, ESI+). To the solution of 44 (0.92 g, 5.1 mmol) in MeOH (50 mL) was added Pd/C (0.5 g) and the hydrogenation was conducted at one atmosphere and rt for 2.5 h to provide the desired product 45 as a solid (0.68 g, yield 88%). 1H NMR (300 MHz, DMSO-d6): delta 8.78 (s, 1H), 7.10 (t, 1H), 6.47 (d, 1H), 6.39 (d, 1H), 5.32(s, 2H), 4.82(s, 2H) ppm. MS: m/z = 150 (M+1, ESI+). To a mixture of 45 (800 mg, 5.37 mmol) and K2CO3 (2.23 g, 0.0161 mol) in N,N-dimethylacetamide (17.9 mL) was added ethyl bromoacetate (0.623 mg, 3.76 mmol). The reaction was stirred overnight at rt. It was diluted with water and extracted with EA. The organic layer was washed with 2 N HCl, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography eluted with EA/DCM (10%) to give the desired product 46 as a solid (380 mg, yield 30%). 1H NMR (300 MHz, DMSO-d6): delta 8.98 (s, 1H), 7.20 (t, 1H), 6.60 (d, 1H), 6.25 (d, 1H), 5.63 (s, 1H), 4.86 (s, 2H), 4.14 (q, 2H), 3.80 (s, 2H), 1.20 (t, 3H) ppm. The mixture of 46 (30 mg, 0.127 mmol) and LiOH?H2O(10.7 mg, 0.255 mmol) in THF/MeOH/H2O = 3:2:1 (0.51 mL) was stirred for 2 h. The mixture was purified by preparative TLC (EA/PE = 1:1) to give the desired final compound 5 as a solid (11 mg, yield 42.3%).
60%
2-Methyl-6-nitrobenzenamine (30.4g, 0.2mol) was suspended in water (250ml) and HBr (100ml, 40% aq.), and the mixture was heated to reflux for 10 min. Then the mixture was cooled to O0C and NaNO2 (13.8g, 0.2mol) in water (80ml) was added dropwise at such a rate that the temperature did not exceed 50C. The dizaonium solution was stirred for a further 30 min at 0-50C and then added slowly to a stirred mixture of CuBr (28.7g, 0.2mol) in HBr (80ml) and water (150ml) at roomtemperature. The mixture was stirred at room temperature for 30 min and then on a steam-bath for Ih. The mixture was washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography with petroleum ether as eluent to give a pale yellow solid (25.9g, yield 60%).
60%
The suspension of 2-methyl-6-nitroaniline (30.4 g, 0.2 mol) in water (250 mL) and HBr (100 mL, 40% aq.) was refluxed for 10 min and then was cooled to 0 C. A solution of NaNO2 (13.8 g, 0.2 mol) in water (80 mL) was added dropwise at < 5 C. The diazonium solution was stirred for a further 30 min at 0-5 C and then added slowly to a stirring mixture of CuBr (28.7 g, 0.2 mol) in HBr (80 mL) and water (150 mL) at room temperature. The mixture was stirred at room temperature for 30 min and then on a steam-bath for 1h. The mixture was washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether as eluent to give 2-bromo-1-methyl-3-nitrobenzene as a pale yellow solid (25.9 g, yield 60%). The mixture of 2-bromo-1-methyl-3-nitrobenzene (14.3 g, 0.066 mol), NBS (17.7g, 0.099 mol) and AIBN (0.3 g, 1.8 mmol) in CCl4 (250 mL) was refluxed overnight. The mixture was filtered and the filtrate was concentrated to give 2-bromo-1-(bromomethyl)-3-nitrobenzene as a red liquid (21 g). The mixture of 2-bromo-1-(bromomethyl)-3-nitrobenzene (21 g) and NaOAc (16.4 g, 0.2 mol) in DMF (300 mL) was stirred at 70 C overnight, and then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether/ethyl acetate (20/1, v/v) as eluent to give 2-bromo-3-nitrobenzyl acetate as a white solid (7.7 g, 42% over two steps).To a solution of 2-bromo-3-nitrobenzyl acetate (16.5 g, 0.06 mol) in 1,4-dioxane (250 mL) was bubbled with nitrogen for 20 min. Potassium acetate (20.6 g, 0.21 mol), Pd(dppf)Cl2 (3.92 g, 4.8 mmol) and bis(pinacolato)diboron (22.9 g, 0.09 mol) were added and the reaction mixture was stirred under N2 at 95 C for 20 h. The reaction mixture was then cooled and concentrated. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography with petroleum ether/ethyl acetate (20/1, v/v) as eluent to give 3-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate as a yellow oil (9.9 g, 51%). LC-MS (ESI) m/z 322 [M+1]+, (calcd MS 321.1).To a solution of 3-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (9.9 g, 0.03 mol) in methanol (300 mL) was added NaOH (5 N, 12 mL, 0.06 mol). The reaction mixture was stirred and refluxed under nitrogen for 24 h. It was then concentrated under vacuum and the residue was dissolved in THF (100 mL). HCl (5 N, 60 mL, 0.3 mol) was added and the reaction mixture was stirred and heated at 40C for 16 h. It was cooled, diluted with EtOAc and poured into brine. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was recrystallized from the mixed solvents of ethyl acetate and petroleum ether to give 7-nitrobenzo[c][1,2]oxaborol-1(3H)-ol as a yellow solid (3.8 g, yield 71%). LC-MS (ESI) m/z 180 [M+1]+, (calcd MS 179.0). 1H NMR (300 MHz, DMSO-d6): delta 8.99 (s, 1H), 8.01 (d, 1H), 7.81 (m, 2H), 5.05 (s, 2H).To a solution of 7-nitrobenzo[c][1,2]oxaborol-1(3H)-ol (0.92 g, 5.1 mmol) in MeOH (50 mL) was added Pd/C (0.5 g) and the hydrogenation was conducted at one atmosphere and room temperature for 2.5 h to provide the desired product 2e as a solid (0.68 g, yield 88%). LC-MS (ESI) m/z 150 [M+1]+, (calcd MS 149.1). 1H NMR (300 MHz, DMSO-d6): delta 8.78 (s, 1H), 7.10 (t, 1H), 6.47 (d, 1H), 6.39 (d, 1H), 5.32(s, 2H), 4.82(s, 2H).
With hydrogenchloride; copper(I) bromide; sodium nitrite; In water; hydrogen bromide;
Method M 2-Bromo-[1,1'-biphenyl]-3-methanol was prepared as follows: A stirred solution of 2-methyl-6-nitroaniline (75.0 g, 0.493 mole) and 40 ml of hydrochloric acid (48% solution) in 135 ml of water was cooled to 0. During a one hour period a solution of sodium nitrite (36.2 g, 0.51 mole) in 60 ml of water was added to the reaction mixture. The mixture was suction filtered through a sintered glass funnel, collecting the filtrate in a flask cooled by a dry ice-acetone bath. The filtrate was placed in a jacketed addition funnel cooled by a dry ice-acetone bath. During a five minute period this solution was added to a stirred mixture of cuprous bromide (77.8 g, 0.51 mole) in 165 ml of hydrobromic acid (48% solution). After complete addition, the mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then steam distilled. The distillate was extracted with methylene chloride and the extract washed with 2 N aqueous sodium hydroxide, followed by several portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated under reduced pressure to give 1-bromo-2-methyl-6-nitrobenzene (17 g) as a solid.
With sodium hydroxide; sodium nitrate; copper(I) bromide; In water; hydrogen bromide;
Step A Synthesis of 2-bromo-3-nitrotoluene A stirred solution of 75.0 grams (0.493 mole) of 2-methyl-6-nitroaniline and 40 ml of aqueous 48% hydrobromic acid in 135 ml of water was cooled to 0 C. and a solution of 36.2 grams (0.510 mole) of sodium nitrate in 60 ml of water was added dropwise during a one hour period. Upon complete addition the mixture was filtered through glass wool into a large dropping funnel. This solution was added dropwise to a second solution of 77.8 grams (0.542 mole) of cuprous bromide in 165 ml of aqueous 48% hydrobromic acid that was being stirred at 15 C. Upon complete addition the reaction mixture was stirred at 15 C. for a few minutes then was allowed to warm to ambient temperature where it stirred for one hour. The reaction mixture stood for 16 hours then was heated to 60 C. where it stirred for two hours. The reaction mixture was subjected to steam distillation. The distillate was extracted with three portions of 150 ml each of methylene chloride. The combined extracts were washed with two portions of 150 ml each of aqueous 2 N sodium hydroxide and five portions of 200 ml each of an aqueous solution saturated with sodium chloride (until the wash was pH-7). The organic layer was dried with magnesium sulfate while being slurried with decolorizing carbon. The mixture was filtered and the filtrate concentrated under reduced pressure to give 6.6 grams of 2-bromo-3-nitrotoluene; mp 36-41 C. The nmr spectrum was consistent with the proposed structure. The pot residue from the steam distillation was extracted with 400 ml of methylene chloride. The extract was washed with aqueous 2 N sodium hydroxide then with an aqueous solution saturated with sodium chloride (until the salt wash was pH-7). The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 18.0 grams of 2-bromo-3-nitrotoluene, which was combined with the 6.6 grams of above to give a total yield of 24.6 grams.
With copper(I) bromide; sodium nitrite; In water; hydrogen bromide;
Method M 2-Bromo-[1,1'-biphenyl]-3-methanol was prepared as follows: A stirred solution of 2-methyl-6-nitroaniline (75.0 g, 0.493 mole) and 40 ml of hydrobromic acid (48% solution) in 135 ml of water was cooled to 0. During a one hour period a solution of sodium nitrite (36.2 g, 0.51 mole) in 60 ml of water was added to the reaction mixture. The mixture was suction filtered through a sintered glass funnel, collecting the filtrate in a flask cooled by a dry ice-acetone bath. The filtrate was placed in a jacketed addition funnel cooled by a dry ice-acetone bath. During a five minute period this solution was added to a stirred mixture of cuprous bromide (77.8 g, 0.51 mole) in 165 ml of hydrobromic acid (48% solution). After complete addition, the mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then steam distilled. The distillate was extracted with methylene chloride and the extract washed with 2 N aqueous sodium hydroxide, followed by several portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated under reduced pressure to give 1-bromo-2-methyl-6-nitrobenzene (17 g) as a solid.
With Iodine monochloride; acetic acid at 30℃; for 3h;
98%
With sodium acetate; Iodine monochloride; acetic acid at 80℃; for 0.833333h;
6.6.3.3; 3.3.13.13
Example 3; Synthesis of Compounds of Formula (I); Spiro Compounds; [00443] 4-Iodo-2-methyl-6-nitroaniline; To a mixture of 2-methyl-6-nitroaniline(106.5 g, 0.7 mol) and NaOAc (63.2 g, 0.77 mol) in acetic acid (525 mL) was added a solution of ICl (125 g, 0.77 me ι. The mixture was heated at 80 °C for 50 min and poured into H2O (2100 mL). After stayed at the room temperature for 16 h, the mixture was filtered to furnish yellow solid that was washed with H2O (3 x 350 mL). Drying under reduced pressure at 40 °C for 48 h afforded the title compound (191 g, 98%). 1H NMR (CDCl3) δ 2.22 (s, 3H), 6.20 (br s, 2H NH), 7.53 (s, IH)3 8.34 (s, IH). ESI-MS mlz 279 (MH+).; Example 13; Synthesis of Compounds According to Formula (6);[00628] 4-Iodo-2-methyl-6-nitroaniline; To a mixture of 2-methyl-6-nitroaniline(106.5 g, 0.7 mol) and NaOAc (63.2 g, 0.77 mol) in acetic acid (525 mL) was added a solution of ICl (125 g, 0.77 mol) in acetic acid (350 mL). The mixture was heated at 80 °C for 50 min and poured into H2O (2100 mL). After stayed at the room temperature for 16 h, the mixture was filtered to furnish yellow solid that was washed with H2O (3 x 350 mL). Drying under reduced pressure at 40 °C for 48 h afforded the title compound (191 g, 98%). 1H NMR (CDCl3) δ 2.22 (s, 3H), 6.20 (br s, 2H NH), 7.53 (s, IH), 8.34 (s, IH). ESI-MS mlz 279 (MH+).; 4-Iodo-2-methyl-6-nitroaniline; To a mixture of 2-methyl-6-nitroaniline(106.5 g, 0.7 mol) and NaOAc (63.2 g, 0.77 mol) in acetic acid (525 mL) was added a solution of ICl (125 g, 0.77 mol) in acetic acid (350 mL). The mixture was heated at 80 °C for 50 min and poured into H2O (2100 mL). After stayed at the room temperature for 16 h, the mixture was filtered to furnish yellow solid that was washed with H2O (3 x 350 mL). Drying under reduced pressure at 40 °C for 48 h afforded the title compound (191 g, 98%). 1H NMR (CDCl3) δ 2.22 (s, 3H), 6.20 (br s, 2H NH), 7.53 (s, IH), 8.34 (s, IH). ESI-MS mlz 279 (MH+).
97%
With N-iodo-succinimide; acetic acid at 50 - 55℃; for 6h; Inert atmosphere;
With Iodine monochloride; acetic acid
With Iodine monochloride; sodium hydrogencarbonate In methanol; dichloromethane at 20℃; for 6h;
With tert.-butylnitrite; copper(l) chloride; In acetonitrile; at 65℃; for 3.0h;Inert atmosphere;
A solution of 2-methyl-6-nitroaniline (25 g, 0.16 mol) in acetonitrile (300 mL) was added to a solution of ie/ -butyl nitrite (34 g, 0.33 mol, 39 mL) and Cu(I)Cl (24 g, 0.25 mol) in acetonitrile (300 mL). The reaction mixture was then heated to 65 C under an atmosphere of N2 and was stirred at that temperature for 3 h. The reaction mixture was cooled to ambient temperature, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by silica-gel column chromatography (petroleum ether/EtOAc, 100:1) to give 2-chloro-l-methyl- 3 -nitrobenzene as a yellow oil (23 g, yield: 82%) 1H NMR (400 MHz, DMSO-i) d: 7.84 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.50-7.46 (m, 1H), 2.44 (s, 3H).
With n-Butyl nitrite; copper(l) chloride; In acetonitrile; at 10 - 30℃; for 3.0h;
A solution of 0.2 mol of 2-amino-3-methyl-1-nitrobenzene was dissolved in 200 ml of acetonitrile. 0.3 mol of anhydrous copper chloride was added. Stirring. 0.3 mol of butyl nitrite was added dropwise at 10 C. About 3 hours after the completion of dropping, the temperature of the system was raised to 30 C. Reaction to the system no nitrogen release. The acetonitrile was then distilled off under reduced pressure. The residue was poured into water. Extracted with ethyl acetate, dry. The solvent was distilled off. Gave 2-chloro-3-methyl-1-nitrobenzene crude 22.1g. It was used directly in the next reaction without further purification.
With N-chloro-succinimide; acetic acid; at 0.55 - 50℃;Inert atmosphere;
4-Chloro-2-methyl-6-nitroaniline (B) To a 2-necked round-bottom flask equipped with an addition funnel, a thermometer and a magnetic stir bar under an atmosphere of argon, was added 2-methyl-6-nitroaniline (12.97 g; 85.23 mmol) and glacial acetic acid (35 mL). The suspension was placed in a pre-heated oil bath at 50 C. to produce a red solution. To the addition funnel was added a suspension of 11.95 g N-chlorosuccinimide (NCS) in about 45 mL of acetic acid. The NCS suspension was added dropwise over about 15 minutes while maintaining the temperature at about 55 C. After the addition was complete, the addition funnel was rinsed with acetic acid (ca. 5 mL) and added to the reaction mixture. A brown homogeneous solution resulted during the course of the reaction. The progress of the reaction was followed by TLC (eluent: methylene chloride). Upon completion of the reaction, the reaction mixture was cooled to room temperature and poured into 100 mL of water and then cooled in an ice bath. The solids were filtered on paper under vacuum, and rinsed with 130 mL of water. The solids were dried in the filter funnel under vacuum to yield 13.3 g of the title compound as an orange-red solid. 1H NMR (400 MHz, DMSO-d6) delta 7.82 (d, J=2.2 Hz, 1H), 7.38 (br. s, 1H), 7.23 (br. s., 2H), 2.17 (s, 3H). MS (ESI+) m/z=187 (M+1). This material was used in the subsequent reactions without further purification.
13.3 g
With N-chloro-succinimide; acetic acid; at 50 - 55℃;Inert atmosphere;
To a 2-necked round-bottom flask equipped with an addition funnel,a thermometer and a magnetic stir bar under an Argon atmosphere wasadded 12.97 g (85.23 mmol) of 2-methyl-6-nitroaniline and 35 mLglacial acetic acid. The suspension was placed in a pre-heated oil bathat 50 C to produce a red solution. To the addition funnel was added asuspension of 11.95 g N-chlorosuccinimide (NCS) in ca. 45 mL of aceticacid. The NCS suspension was added dropwise over ca 15 min whilemaintaining the temperature around 55 C. After the addition wascomplete, the addition funnel was rinsed with acetic acid (ca. 5 mL) andadded. A brown homogeneous solution resulted during the course of thereaction. The progress of the reaction was followed by TLC using methylenechloride as the elutant. Upon completion of the reaction, thereaction mixture was cooled to room temperature, poured into 100 mLof water and cooled in an ice bath. The solids were filtered on paperunder vacuum, and rinsed with a total of 130 mL of water. The solidswere dried in air in the filter funnel under vacuum to yield 13.3 g of 4-chloro-2-methyl-6-nitroaniline as an orange-red solid. 1H NMR(400 MHz, DMSO-d6) delta 7.82 (d, J=2.2 Hz, 1H), 7.38 (br. s, 1H), 7.23(br. s., 2H), 2.17 (s, 3H). MS (ESI+) m/z=187 (M+1). This materialwas used in the subsequent reaction without further purification.
With N-chloro-succinimide; acetic acid; at 50 - 55℃;Inert atmosphere;
To a 2-necked round-bottom flask equipped with an addition funnel, a thermometer and a magnetic stir bar under an Argon atmosphere was added 12.97 g (85.23 mmol) of 2- methyl-6-nitroaniline and 35 ml glacial acetic acid. The suspension was placed in a pre- heated oil bath at 50 C to produce a red solution. To the addition funnel was added a suspension of 11.95 g N-chlorosuccinimide (NCS) in ca.45 mL of acetic acid. The NCS suspension was added dropwise over ca.15 minutes while maintaining the temperature around 55 C. After the addition was complete, the addition funnel was rinsed with acetic acid (ca.5 mL) and added. A brown homogeneous solution resulted during the course of the reaction. The progress of the reaction was followed by TLC using methylene chloride as the elutant. Upon completion of the reaction, the reaction mixture was cooled to room temperature, poured into 100 mL of water and cooled in an ice bath. The solids were filtered on paper under vacuum, and rinsed with a total of 130 mL of water. The solids were dried in air in the filter funnel under vacuum to yield 13.3 g of 4-chloro-2-methyl-6-nitroaniline as an orange-red solid. 1H NMR (400 MHz, DMSO-d6) 7.82 (d, J = 2.2 Hz, 1H), 7.38 (br. s, 1H), 7.23 (br. s., 2H), 2.17 (s, 3H). MS (ESI+) m/z = 187 (M+1). This material was used in the subsequent reaction without further purification.
To a stirred solution of step-a-c product (10 g, 0.065 mol) in acetic acid (470 ml, 47 times), a solution of sodium nitrite (1.54 g, 0.06 mol, 1.1 eq) in water (9 ml) was added and the reaction mass was stirred for 30 - 45 min. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, Rr-0.7). On completion of the reaction, acetic acid was distilled off and the residue obtained was taken in ice water (200 ml). Solid formed was filtered, washed with cold water and dried to yield the required product as an yellow colored solid (10 g, 98% yield).
97%
With acetic acid; sodium nitrite; In water; at 20℃; for 0.333333h;Inert atmosphere;
To a solution of 2-methyl-6-nitroaniline (5.00 g, 32.80 mmol) in acetic acid (250 mL)was added a solution of sodium nitrite (2.50 g,36.10 mmol) in water (5 mL). The mixture was stirred for20 min at room temperature. Yellow precipitate formedduring reaction which was filtered and discarded. Thecombined solution was evaporated under reduced pressureand cold water was added to the residue. Pale yellow solidwas formed, filtered, rinsed with cold water and driedunder vacuum to afford 7-nitro-1H-indaozle. Yield = 97%(5.22 g); 1H-NMR (CDCl3, 300 MHz) delta 11.4 (1H, br, NH),8.40 (1H, d, J = 9.0 Hz, Ar), 8.31 (1H, s, Ar), 8.19 (1H, d,J = 6.0 Hz, Ar), 7.37 (1H, dd, J = 6.0 Hz andJ = 9.0 Hz).
With hydrogen bromide; dihydrogen peroxide; In ethanol; water; at 60℃; for 1h;Product distribution / selectivity;
Aqueous hydrobromic acid (48 wt%, 1.1 molar equivalents) was added at room temperature to an 18.1 wt% solution of 2-methyl-6-nitroaniline (6O g) in ethanol/water (70:30 v/v). The mixture was warmed to 60 C and hydrogen peroxide (30 wt% in water, 1.2 molar equivalents) was added. The mixture was stirred at 60 C for 1 h and the cooled to room temperature. The precipitated product was filtered off, washed with ethanol and dried. Yield: 97.7%
With potassium hydroxide; hydrogen;palladium; In tetrahydrofuran; methanol; concentrated aqueous hydrochloric acid; ethanol; water;
EXAMPLE 86 6-[[(4-Methyl-1H-benzimidazol-2-yl)-thio]methyl]-2-pyridinamine hemihydrate A solution of 20 g (0.13 mole) of 2-methyl-6-nitroaniline in 22.9 ml of concentrated aqueous hydrochloric acid, 200 ml of tetrahydrofuran, and 350 ml of methanol was hydrogenated at room temperature using 25 psi. of hydrogen gas over 2.0 g of 5% palladium on carbon. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 150 ml of ethanol and neutralized with 17.2 g (0.26 mole) of potassium hydroxide dissolved in 30 ml of water. Potassium ethylxanthate (23g, 0.155 mole) was added and the mixture was heated at reflux for 18 hours. Upon cooling, a solid was collected, washed with water, and air dried to yield 6.2 g of 2-mercapto-4-methylbenzimidazole, as confirmed by the nmr and infrared spectra.
With potassium hydroxide;palladium; In tetrahydrofuran; methanol; concentrated aqueous hydrochloric acid; ethanol; water;
EXAMPLE 10 2-[(imidazo[1,2-a]pyridin-8-ylmethyl)thio]-4-methyl-1H-benzimidazole STR19 A solution of 20 g (0.13 mole) of 2-methyl-6-nitroaniline in 22.9 ml of concentrated aqueous hydrochloric acid, 200 ml of tetrahydrofuran, and 350 ml of methanol was hydrogenated at room temperature using 25 p.s.i. of hydrogen gas over 2.0 g of 5% palladium on carbon. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 150 ml of ethanol and neutralized with 17.2 g (0.26 mole) of potassium hydroxide dissolved in 30 ml of water. Potassium ethylxanthate (23 g, 0.155 mole) was added and the mixture was heated at reflux for 18 hours. Upon cooling, a solid was collected, washed with water, and air dried to yield 6.2 g of 2-mercapto-4-methylbenzimidazole, as confirmed by the nmr and infrared spectra.
With potassium iodide; sulfuric acid; sodium nitrite; In ice-water; ethanol; dichloromethane;
PREPARATION EXAMPLE 3 Synthesis of 2-Iodo-3-nitrotoluene (6) In a 500 ml three-necked flask was charged 110 g (0.72 mole) of 2-amino-3-nitrotoluene (5) as obtained in Preparation Example 2, and 260 ml of concentrated sulfuric acid was added thereto, followed by stirring at 0 C. To the solution was added 74.8 g (1.08 mole) of sodium nitrite over 45 minutes, and the solution was stirred at 0 C. for 4 hours, whereby the solution became a dark brown suspension. The reaction mixture was poured into 3 l of ice-water, and 1 l of an aqueous 53% potassium iodide was added thereto. After stirring at 80 C. for 10 hours, the reaction mixture was treated with 100 g of sodium hydrogensulfite. A supernatant was removed, and insoluble matters were extracted thrice with 500 ml of dichloromethane. An organic layer was neutralized and washed with a saturated sodium hydrogencarbonate aqueous solution, washed with distilled water, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain a yellowish brown crude crystal. Recrystallization of the crude crystal from 150 ml of 99% ethanol gave 2-iodo-3-nitrotoluene (6) as a pale yellow crystal having a melting point of 64.8 to 65.2 C. and an 84% yield (inclusive of secondary crystals recovered from the filtrate after recrystallization).
1.b b.
b. N-ethoxalyl-2-nitro-6-methylaniline To a stirred solution of 2-nitro-6-methylaniline (10 g, 65 mmol) and triethylamine (11 ml, 80 mmol) in THF (80 ml) was dropwise added a solution of ethoxalyl chloride (9 ml, 80 mmol). After completion of the addition the mixture was brought to reflux by external heating. After 3 h the mixture was cooled to room temperature and the precipitated triethylammonium chloride was filtered off. The filtrate was evaporated to give the crude product as an oil. Purification (SiO2 /ether:pentane, 1:1) gave the pure title compounds as an oil. In a similar manner were obtained the following N-ethoxalyl anilines by reaction between ethoxalyl chloride and the corresponding anilines: N-ethoxalyl-N-(2-methoxybenzyl)-2-nitroaniline. Oil N-ethoxalyl-N-(4-methoxybenzyl)-2-nitroaniline. Oil
With hydrogenchloride; sodium nitrite; In sodium hydrogencarbonate; ethyl acetate; toluene;
Step 1 Production of 2-cyano-3-nitrotoluene 76.07 g (500 mmol) of 2-amino-3-nitrotoluene were added to 100 g (990 mmol) of 36% hydrochloric acid and 500 g of ice followed by stirring vigorously at 0 C. 80 ml of an aqueous solution containing 37.95 g (550 mmol) of sodium nitrite was then slowly dropped in while holding the temperature to 0-5 C. Following completion of dropping, 100 ml of toluene were added followed by stirring for 30 minutes at 0 C. The reaction solution was placed in an ice-NaCl bath followed by slowly adding sodium bicarbonate while stirring vigorously to neutralize the pH to about 6 (diazonium salt solution (1)). An aqueous solution (550 ml) containing 260.5 g (4000 mmol) of potassium cyanide was slowly added at 0 C. to an aqueous solution (650 ml) containing 99.0 g (1000 mmol) of copper (I) chloride followed by stirring for 90 minutes and then adding 200 ml of ethyl acetate. The diazonium salt solution (1) prepared above was then dropped into this solution over the course of 30 minutes while holding the temperature to 0-5 C. The solution was then stirred for 12 hours in an ice bath and then warmed to room temperature. After extracting the reaction solution with ethyl acetate and washing the organic phase with water, it was dried with magnesium sulfate followed by concentrating the solvent under reduced pressure. The residue was then purified by silica gel column chromatography (hexane:ethyl acetate=20:1?10:1?7:1?5:1?3:1) to obtain 58.63 g (362 mmol) of the target compound (yield: 72%). 1H-NMR (270 MHz, CDCl3) (ppm): 7.68 (2H, m), 8.13 (1H, m), 2.715 (3H, s)
72%
With hydrogenchloride; sodium nitrite; In sodium hydrogencarbonate; ethyl acetate; toluene;
Step 1 Production of 2-cyano-3-nitrotoluene 76.07 g (500 mmol) of 2-amino-3-nitrotoluene were added to 100 g (990 mmol) of 36% hydrochloric acid and 500 g of ice followed by stirring vigorously at 0C. 80 ml of an aqueous solution containing 37.95 g (550 mmol) of sodium nitrite was then slowly dropped in while holding the temperature to 0-5C. Following completion of dropping, 100 ml of toluene were added followed by stirring for 30 minutes at 0C. The reaction solution was placed in an ice-NaCl bath followed by slowly adding sodium bicarbonate while stirring vigorously to neutralize the pH to about 6 (diazonium salt solution (1)). An aqueous solution (550 ml) containing 260.5 g (4000 mmol) of potassium cyanide was slowly added at 0C to an aqueous solution (650 ml) containing 99.0 g (1000 mmol) of copper (I) chloride followed by stirring for 90 minutes and then adding 200 ml of ethyl acetate. The diazonium salt solution (1) prepared above was then dropped into this solution over the course of 30 minutes while holding the temperature to 0-5C. The solution was then stirred for 12 hours in an ice bath and then warmed to room temperature. After extracting the reaction solution with ethyl acetate and washing the organic phase with water, it was dried with magnesium sulfate followed by concentrating the solvent under reduced pressure. The residue was then purified by silica gel column chromatography (hexane:ethyl acetate = 20:1?10:1?7:1?5:1?3:1) to obtain 58.63 g (362 mmol) of the target compound (yield: 72%). 1H-NMR (270 MHz, CDCl3) (ppm): 7.68 (2H,m), 8.13 (1H,m), 2.715 (3H,s)
In a solution of H2SO4/H2O (4.2 mL/14.5mL, 78.8 mmol), compound 1 (3 g, 19.7 mmol) was suspended. After cooling, diazotization was accomplished by adding NaNO2/H2O (1.4 g/5 mL, 20.4 mmol). Then to a cold solution (-50C) was added KSCN/H2O (2.48 g/5 mL, 25.61 mmol) and CuSCN (2.3 g, 19.1 mmol). After standing overnight, the mixture was heated to 600C for 5 minutes, cooled and extracted with EA. The mixture was dried over MgSO4, concentrated and purified by chromatography to give an orange solid (2.5 g). Yield: 65%. 1HNMR (400 MHz, CDCl3): delta (ppm): 7.83 (IH, d, Ar-H), 7.53-7.65 (2H, m, Ar-H), 2.78 (3H, s, CH3-).
With indium; acetic acid In ethyl acetate for 2.5h; Reflux; Inert atmosphere;
4.2. General procedure for the indium-mediated reductive reaction of 2-nitroanilines or 1,2-dinitroarenes with trimethyl orthoesters to benzimidazoles
General procedure: 2-Nitroaniline derivative (1 mmol) was added to a mixture of indium powder (574 mg, 5.0 mmol for 2-nitroaniline, 918 mg 8.0 mmol for 1,2-dinitroarene), and acetic acid (0.572 mL, 10 mmol) in ethyl acetate (2 mL), followed by the addition of trimethyl orthoester (2.0 mmol) in ethyl acetate (3 mL for 2-nitroaniline; 8 mL for 1,2-dinitroarene). The reaction mixture was stirred at reflux under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, poured into 10% NaHCO3 (30 mL), and then extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was eluted with ethyl acetate/hexane (v/v=10/90) for 2-phenylbenzimidazole derivatives or methanol/dichloromethane (v/v=1/99) for 2-methylbenzimidazole derivatives through a silica gel column to give the corresponding benzimidazoles. The structures of the benzimidazoles were characterized by 1H NMR, 13C NMR, FTIR, and GC-MS, and were mostly known compounds. HRMS data were reported in addition for unknown compounds.
With indium; acetic acid; In ethyl acetate; for 1h;Reflux; Inert atmosphere;
General procedure: 2-Nitroaniline derivative (1 mmol) was added to a mixture of indium powder (574 mg, 5.0 mmol for 2-nitroaniline, 918 mg 8.0 mmol for 1,2-dinitroarene), and acetic acid (0.572 mL, 10 mmol) in ethyl acetate (2 mL), followed by the addition of trimethyl orthoester (2.0 mmol) in ethyl acetate (3 mL for 2-nitroaniline; 8 mL for 1,2-dinitroarene). The reaction mixture was stirred at reflux under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, poured into 10% NaHCO3 (30 mL), and then extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was eluted with ethyl acetate/hexane (v/v=10/90) for 2-phenylbenzimidazole derivatives or methanol/dichloromethane (v/v=1/99) for 2-methylbenzimidazole derivatives through a silica gel column to give the corresponding benzimidazoles. The structures of the benzimidazoles were characterized by 1H NMR, 13C NMR, FTIR, and GC-MS, and were mostly known compounds. HRMS data were reported in addition for unknown compounds.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; XPhos; In N,N-dimethyl acetamide; at 110℃; for 3.0h;Inert atmosphere;
Synthesis of 6-(2,6-dichloro-3 ,5-dimethoxyphenyl)-N- (2-methyl-6-nitrophenyl)quinazolin-2-amine. 2-Chloro-6-(2,6-dichloro-3 ,5-dimethoxyphenyl)quinazoline (35) (5 g, 13.5 mmol), 2-methyl-6- nitroaniline (3.09 g, 20.3 mmol), Cs2CO3 (13.2 g, 40.6 mmol), Pd2(dba)3 (1.24 g, 1.35 mmol), and 2-Dicyclohexylphosphino-2?,4?,6?-triisopropylbiphenyl (Xphos) (1.29 g, 2.71 mmol) were taken up in DMA (100 ml) and purged with N2 for 5 minutes. The reaction mixture was heatedto 110C in for 3 hours. After cooling to room temperature the reaction mixture was diluted with DCM (500 ml) and washed with 10% HC1 three times (3 x 300 ml) and brine three times. The organic mixture was dried over sodium sulfate and loaded directly onto silica gel and purified using 0-100% EtOAc/Hexanes gradient. 6-(2,6-dichloro-3 ,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine was recovered as a yellow solid (5.5 g, 81% yield). MS (ES+) C23H,8C12N404, 485 [M + H].
With sodium hydroxide; In ethanol; water; at 70℃; for 2h;Green chemistry;
General procedure: TUD (20 mmol) was added in batches to a solution of substituted 2-nitroanilines (5 mmol) and NaOH (20 mmol) in H2O (15 mL) and EtOH (5 mL) at 70 C. The reaction mixture was stirred for a certain period of time as required to complete the reaction (monitored byTLC). After cooling, 10% NaOH solutions were added until pH = 9-10, the precipitated solid was filtered off and washed with water to obtain crude product. The crude product was recrystallised from water to give a white solid. The physical and spectra data of the compounds 2a-h were as follows.
1-methyl-5-((2-methyl-6-nitrophenyl)amino)-1H-pyrazole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With potassium hydroxide In N,N-dimethyl-formamide at 100℃; for 1h; Inert atmosphere;
General Procedure 1
General procedure: A magnetically stirred solution of pyrazole 4 (500 mg, 3.46 mmol) in DMF (7 mL)was treated with KOH (387 mg, 6.90 mmol) and nitroaniline 7a-e, 10 or 13a-b (3equiv., 10.38 mmol) then heated at 100 °C for 1 h. The resulting mixture was cooledto room temperature then treated with NH4Cl (100 mL of a saturated aqueoussolution) and extracted with ethyl acetate (3 × 25 mL). The combined organic phaseswere washed with brine (1 × 50 mL) before being dried (MgSO4), filtered andconcentrated under reduced pressure to afford a yellow oil. Subjection of this residueto flash column chromatography (silica, 1:4 → 1:1 v/v ethyl acetate/n-hexane gradientelution) and concentration of the relevant fractions afforded the target pyrazole 8a-e,11 or 14a-b.
4-methyl-di(2-pyridyl)benzo[g]quinoxaline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With indium; acetic acid In methanol at 50℃; for 3h; Inert atmosphere;
4.2. General procedure for the indium-mediated reductivecyclization of 2-nitroanilines to prepare quinoxaline
General procedure: 4.2. General procedure for the indium-mediated reductivecyclization of 2-nitroanilines to prepare quinoxalines A mixture of the 2-nitroaniline derivative (1.0 mmol), dione (1.0or 2.0 mmol), indium (0.574 g, 5.0 mmol), and acetic acid (0.300 g,5 mmol or 0.600 g,10 mmol) or indium chloride (0.221 g,1 mmol or0.265 g,1.2 mmol) in methanol (5 mL) or toluene (5 mL) was stirredat 50 C, 80 C, or reux under a nitrogen atmosphere. After com-pletion of the reaction, the reaction mixture was diluted with ethylacetate (30 mL), ltered through Celite, and the ltrate was pouredinto 10% NaHCO3 (30 mL) and extracted with ethyl acetate(30 mL3). The combined organic extracts were dried over MgSO4,ltered, and concentrated. The residue was eluted with ethyl ace-tate/hexane (v/v10/90) through a silica gel column to give thecorresponding pure quinoxaline. Quinoxaline structures werecharacterized by 1H NMR, 13C NMR, FTIR, and GCeMS, and weremostly known compounds. For unknown compounds, elementalanalysis data were additionally obtained. 4.2.1. 2,3-Dimethylquinoxaline (5).19,31aef Yield 87%. Yellow solid,mp 109e110 C (lit.31f mp 105 C). TLC (10% ethyl acetate/hexane) Rf0.30; 1H NMR (400 MHz, CDCl3) d 7.91 (dd, 2H, J6.3, 3.5 Hz), 7.59(dd, 1H, J6.3, 3.5 Hz), 2.66 (s, 6H); 13C NMR (100 MHz, CDCl3)d 153.4, 141.0, 128.7, 128.2, 23.1; IR (KBr) 3109, 3078, 3030, 2995,2953, 2914, 1490, 1398, 1164 cm1;GCeMS m/z (rel intensity) 158(M, 99), 117 (100), 76 (28), 50 (12).
1-methyl-5-((2-methyl-6-nitrophenyl)amino)-1H-pyrazole-4-carbaldehyde[ No CAS ]
1-methyl-5-((2-methyl-6-nitrophenyl)amino)-1H-pyrazole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide In N,N-dimethyl-formamide at 100℃; for 1h; Inert atmosphere; Overall yield = 44 %; Overall yield = 396 mg; Optical yield = 20 %ee;
General Procedure 1
General procedure: 0172] Compounds Pre-SOC-2, Pre-SOC-3, Pre-SOC-4, Pre-SOC-5 and Pre-SOC- 6, were prepared via General Procedure 1, whereby a magnetically stirred solution of 1 (500 mg, 3.46 mmol) in DMF (7 mL) was treated with KOH (387 mg, 6.90 mmol) and an appropriate nitroaniline (3 equivalents, 10.38 mmol) then heated at 100 °C for 1 hour. The resulting mixture was cooled to room temperature then treated with NH4C1 (100 mL of a saturated aqueous solution) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with brine (1 x 50 mL) before being dried (MgS04), filtered and concentrated under reduced pressure to afford a yellow oil. Subjection of this residue to flash column chromatography (silica, 1:4→ 1: 1 v/v ethyl acetate/n-hexane gradient elution) and concentration of the relevant fractions afforded the target pyrazole.
7-bromo-N-(2-methyl-6-nitrophenyl)thieno[3,2-d]pyrimidine-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A round bottom flask was charged with 2-methyl-6-nitroaniline (42.1 mmol, 6.5 g) andDimethylformamide (130 mL) was added. At 0 ° CSodium hydride (5.7 g, 38.3 mmol) was added thereto, followed by stirring for 30 minutes.Then, 7-bromo-4-chlorothieno [3,2-d] pyrimidine (10.0 g, 38.3 mmol)And the mixture was stirred at room temperature for 1 hour. After completion of the reaction,The reaction was diluted with ethyl acetate,1 N HCl aqueous solution was slowly added dropwise at 0 ° C to neutralize (pH = 7).After separating the water layer and the organic layer, the water layer was extracted with ethyl acetate.The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure.The mixture was purified by MPLC to obtain the desired target compound.
Stage #1: 2-aminotoluene-5-sulfonic acid With acetic acid; zinc(II) oxide at 80℃; for 4h;
Stage #2: With nitric acid at 10 - 12℃; for 2h;
Stage #3: With hydrogenchloride In water at 100℃; for 1h;
1-3 Example 1
Under mechanical stirring, 60.1g (1.00mol) acetic acid was dropped into a mixture of 93.6g (0.50mol) 4-amino-3-methylbenzenesulfonic acid and 4.2g (0.05mol) zinc oxide. After the addition, The temperature was raised to 80°C for 4h. After the reaction is complete, filter through a pad of diatomaceous earth, transfer the filtrate to an ice water bath, and cool to 10-12°C. Add 63ml of concentrated nitric acid (1.00mol HNO3) dropwise, the addition is completed in about 1.5h, the temperature is controlled at 10-12°C during the dropping, and the reaction is maintained at 10-12°C for 30 minutes after the dropping. After nitrification is complete, The reaction solution was poured into 1.5L ice water, and suction filtered to obtain the nitration product solid (without drying). Put the nitration product solid in the flask, add 150ml concentrated hydrochloric acid (1.80mol HCl), React at 100°C for 1h. After the hydrolysis is completed, it is cooled to room temperature, 150 ml of water is added, a solid is separated out, filtered with suction, and the filter cake is dried to obtain 62.1 g of an orange solid with a yield of 82.0% and a purity of 98.2%.
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