* 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.
The 30.0g dinitrobenzene (0.18mmol) dissolved in 180 ml of concentrated sulfuric acid, heating to 80 °C, can keep the temperature in 80-90 °C between, the 44.5gNBS (0.25mol) is divided into nine batches to add to the above-mentioned solution, the reaction continued for 30 min, cooling the caster enters 600 ml ice water, separating white precipitation, filtration, washing, drying to obtain the white solid 3,5-dinitro-bromophenylacetic 41.3g, yield 93.7percent ; measure 1g sodium (43.4mmol) dissolved in methanol to prepare a solution of sodium methylate, will 8.7g3,5-dinitro-bromobenzene (35.2mmol) by adding the above methanol solution of sodium, 45 °C reflux reaction 2h, after cooling to room temperature, using 50mL1N after treatment of the hydrochloric acid solution, dichloromethane is used for extraction, the combined organic was saturated salt water washing 3 times, water-free magnesium sulfate drying, filtering drying solvent, crude column separation (petroleum ether: dichloromethane = 5:1) to obtain white powdery solid 3-methoxy-5-nitrobromobenzene 4.6g, yield: 56.3percent ; the 400mgPd/C adding 2.32g3-methoxy-5-nitro-bromobenzene (10mmol) dissolved in 25 ml methanol with 10 ml acetone in the solution, the hydrogen reaction at room temperature under the conditions of 3h, is filtered to remove Pd/C, to evaporate the solvent, column separation (petroleum ether: ethyl acetate = 4:1) to obtain light yellow solid 1.95g, yield: 96.5percent.
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 889 - 896
[3] Patent: CN103497211, 2016, B, . Location in patent: Paragraph 0075
[4] , 1976, vol. 12, p. 2319 - 2323[5] Zhurnal Organicheskoi Khimii, 1976, vol. 12, # 11, p. 2387 - 2392
2
[ 18242-39-2 ]
[ 16618-67-0 ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium methylate In methanol for 12 h; Reflux
a) To a solution of 1-bromo-3,5-dinitrobenzene (5 g, 20.2 mmol) in methanol (50 ml) was added sodium methoxide (1.3 g, 24.3 mmol, 1.2 eq.) and the mixture was heated to reflux for 12 h and then quenched with 10percent HCl. The solid formed was filtered and dried to afford the compound in 65percent yield (3 g).
Step B. 1-Bromo-3-methoxy-5-nitrobenzene 3,5-Dinitrobromobenzene (1.25 g, 5.06 mmol) was stirred in methanol (12 mL) and a solution of sodium methoxide (0.5 M in methanol, 12.6 mL) was added. The mixture was heated to 60° C. for 2 hours and cooled to RT. The mixture was quenched with hydrogen chloride solution (1 N) and extracted with dichloromethane. Evaporation and purification by silica chromatography using ethyl acetate and hexanes gave the desired compound (1.0 g, 80percent). LCMS for C7H7BrNO3 (M+H)+: m/z=232.1.
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 889 - 896
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905
[3] Patent: US2015/11548, 2015, A1,
[4] Patent: CN103497211, 2016, B,
6
[ 586-10-7 ]
[ 16618-67-0 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 36
[2] Australian Journal of Chemistry, 1981, vol. 34, # 6, p. 1319 - 1324
7
[ 5327-44-6 ]
[ 16618-67-0 ]
Reference：
[1] Australian Journal of Chemistry, 1981, vol. 34, # 6, p. 1319 - 1324
8
[ 88149-47-7 ]
[ 16618-67-0 ]
[ 74137-36-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1925, vol. 44, p. 194
[2] Recueil des Travaux Chimiques des Pays-Bas, 1925, vol. 44, p. 194
9
[ 16618-67-0 ]
[ 16618-68-1 ]
Yield
Reaction Conditions
Operation in experiment
96.5%
With palladium on activated charcoal; hydrogen In methanol; acetone at 20℃; for 3 h;
The 30.0g dinitrobenzene (0.18mmol) dissolved in 180 ml of concentrated sulfuric acid, heating to 80 °C, can keep the temperature in 80-90 °C between, the 44.5gNBS (0.25mol) is divided into nine batches to add to the above-mentioned solution, the reaction continued for 30 min, cooling the caster enters 600 ml ice water, separating white precipitation, filtration, washing, drying to obtain the white solid 3,5-dinitro-bromophenylacetic 41.3g, yield 93.7percent ; measure 1g sodium (43.4mmol) dissolved in methanol to prepare a solution of sodium methylate, will 8.7g3,5-dinitro-bromobenzene (35.2mmol) by adding the above methanol solution of sodium, 45 °C reflux reaction 2h, after cooling to room temperature, using 50mL1N after treatment of the hydrochloric acid solution, dichloromethane is used for extraction, the combined organic was saturated salt water washing 3 times, water-free magnesium sulfate drying, filtering drying solvent, crude column separation (petroleum ether: dichloromethane = 5:1) to obtain white powdery solid 3-methoxy-5-nitro-bromophenylacetic 4.6g, yield: 56.3percent ; the 400mgPd/C adding 2.32g3-methoxy-5-nitro-bromobenzene (10mmol) dissolved in 25 ml methanol with 10 ml acetone in the solution, the hydrogen reaction at room temperature under the conditions of 3h, is filtered to remove Pd/C, to evaporate the solvent, column separation (petroleum ether: ethyl acetate = 4:1) to obtain light yellow solid 1.95g, yield: 96.5percent.
95%
With water; tin(ll) chloride In ethanol for 2 h; Heating / reflux
Example 25 Synthesis of 3-Bromo-5-methoxy-phenylamine (CX) A slurry of 1-bromo-3-methoxy-5-nitrobenzene (9.9 g, 43 mmol) in EtOH (140 ml) was slowly added at RT to SnCl2.2R2O (48 g, 213 mmol). The mixture was refluxed for 2 h, cooled to RT, and poured into ice/water mixture (150 ml). A solution of NaOH (12 M, 250 ml) was added until the pH>12. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in CHCl3 (30 ml) and filtered. The filtrate was concentrated to afford 3-Bromo-5-methoxy-phenylamine CX as an off-white solid (8.2 g, 95percent yield).
92%
With ammonium chloride; zinc In tetrahydrofuran; water at 20℃; for 0.5 h;
b) To a solution of 1-bromo-3-methoxy-5-nitrobenzene (1 g, 4.33 mmol) in THF (10 ml) were added a solution of ammonium chloride (1.83 g, 34.6 mmol, 8 eq.) in water (5 ml) and zinc (1.93 g, 34.6 mmol, 8 eq.). The mixture was stirred at RT for 30 min and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 92percent yield (0.8 g).
54%
With hydrogenchloride; iron; acetic acid In methanol; water at 109℃; for 1 h;
In a 100 mL round bottom flask, 1-bromo-3-methoxynitrobenzene (4.64 g, 20 mmol) and iron powder (5.6 g) were added.100 mmol) of acetic acid/methanol/water mixed solvent (20 mL) was added to the reaction mixture, and a drop of concentrated hydrochloric acid was added to the reaction mixture. The reaction was carried out at 109° C. for 1 h and then at room temperature for 4 h.20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×2), and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate gradient elution) to give yellow The solid was 3-bromo-5-methoxyaniline 2.15g, yield 54percent.
Reference：
[1] Patent: CN103497211, 2016, B, . Location in patent: Paragraph 0074; 0075
[2] Patent: US2007/123527, 2007, A1, . Location in patent: Page/Page column 79
[3] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0788
[4] Organic Letters, 2016, vol. 18, # 11, p. 2774 - 2776
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4889 - 4905
[6] Patent: CN107973727, 2018, A, . Location in patent: Paragraph 0152
[7] Journal of the Chemical Society, 1926, p. 2078
[8] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1977, p. 14 - 17
10
[ 88149-47-7 ]
[ 16618-67-0 ]
[ 74137-36-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1925, vol. 44, p. 194
[2] Recueil des Travaux Chimiques des Pays-Bas, 1925, vol. 44, p. 194
11
[ 16618-67-0 ]
[ 116632-23-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 36
[2] Recueil des Travaux Chimiques des Pays-Bas, 1968, vol. 87, p. 1327 - 1338
[3] Patent: US6458935, 2002, B1,
[4] Patent: US2009/30046, 2009, A1, . Location in patent: Page/Page column 33-34
[5] Patent: WO2009/153313, 2009, A1, . Location in patent: Page/Page column 181
With palladium on activated charcoal; hydrogen; In methanol; acetone; at 20℃; for 3h;
The 30.0g dinitrobenzene (0.18mmol) dissolved in 180 ml of concentrated sulfuric acid, heating to 80 C, can keep the temperature in 80-90 C between, the 44.5gNBS (0.25mol) is divided into nine batches to add to the above-mentioned solution, the reaction continued for 30 min, cooling the caster enters 600 ml ice water, separating white precipitation, filtration, washing, drying to obtain the white solid 3,5-dinitro-bromophenylacetic 41.3g, yield 93.7% ; measure 1g sodium (43.4mmol) dissolved in methanol to prepare a solution of sodium methylate, will 8.7g3,5-dinitro-bromobenzene (35.2mmol) by adding the above methanol solution of sodium, 45 C reflux reaction 2h, after cooling to room temperature, using 50mL1N after treatment of the hydrochloric acid solution, dichloromethane is used for extraction, the combined organic was saturated salt water washing 3 times, water-free magnesium sulfate drying, filtering drying solvent, crude column separation (petroleum ether: dichloromethane = 5:1) to obtain white powdery solid 3-methoxy-5-nitro-bromophenylacetic 4.6g, yield: 56.3% ; the 400mgPd/C adding 2.32g3-methoxy-5-nitro-bromobenzene (10mmol) dissolved in 25 ml methanol with 10 ml acetone in the solution, the hydrogen reaction at room temperature under the conditions of 3h, is filtered to remove Pd/C, to evaporate the solvent, column separation (petroleum ether: ethyl acetate = 4:1) to obtain light yellow solid 1.95g, yield: 96.5%.
95%
With water; tin(ll) chloride; In ethanol; for 2h;Heating / reflux;
Example 25 Synthesis of 3-Bromo-5-methoxy-phenylamine (CX) A slurry of 1-bromo-3-methoxy-5-nitrobenzene (9.9 g, 43 mmol) in EtOH (140 ml) was slowly added at RT to SnCl2.2R2O (48 g, 213 mmol). The mixture was refluxed for 2 h, cooled to RT, and poured into ice/water mixture (150 ml). A solution of NaOH (12 M, 250 ml) was added until the pH>12. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in CHCl3 (30 ml) and filtered. The filtrate was concentrated to afford 3-Bromo-5-methoxy-phenylamine CX as an off-white solid (8.2 g, 95% yield).
92%
With ammonium chloride; zinc; In tetrahydrofuran; water; at 20℃; for 0.5h;
b) To a solution of 1-bromo-3-methoxy-5-nitrobenzene (1 g, 4.33 mmol) in THF (10 ml) were added a solution of ammonium chloride (1.83 g, 34.6 mmol, 8 eq.) in water (5 ml) and zinc (1.93 g, 34.6 mmol, 8 eq.). The mixture was stirred at RT for 30 min and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 92% yield (0.8 g).
54%
With hydrogenchloride; iron; acetic acid; In methanol; water; at 109℃; for 1h;
In a 100 mL round bottom flask, 1-bromo-3-methoxynitrobenzene (4.64 g, 20 mmol) and iron powder (5.6 g) were added.100 mmol) of acetic acid/methanol/water mixed solvent (20 mL) was added to the reaction mixture, and a drop of concentrated hydrochloric acid was added to the reaction mixture. The reaction was carried out at 109 C. for 1 h and then at room temperature for 4 h.20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×2), and the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate gradient elution) to give yellow The solid was 3-bromo-5-methoxyaniline 2.15g, yield 54%.
7.98 g
With ammonium chloride; In methanol; water; at 95℃; for 2h;
To a solution of 1-bromo-3-methoxy-5-nitrobenzene (6) (50.0mmol) in MeOH: H2O (1:1, 150mL) was added carbonyl iron (250mmol, 14.0g) and ammonium chloride (21.4g, 400mmol) at RT and mixture was stirred at 95C for 2h. The mixture was cooled to RT, adjusted to pH 8 with aq. sat. Na2CO3 and filtered over celite (particle size 0.02-0.1mm). The filtrate was concentrated in vacuo, aqueous residue diluted with H2O (200mL) and extracted with EtOAc (3×250mL). The combined organic layer was dried over Na2SO4, concentrated and dried in vacuo to give 3-bromo-5-methoxyaniline as a dark solid (7.98g, 79% over two steps). Rf 0.47 (CH2Cl2 100%); 1H NMR (500MHz, CDCl3) delta=6.46 (1H, t, 4J 1.9), 6.44 (1H, t, 4J 1.8) 6.13 (1H, t, 4J 2.1), 3.74 (3H, s, OCH3), 3.70 (2H, br, NH2); 13C NMR (125MHz, CDCl3) delta=161.3 (C5), 148.6 (C3), 123.3 (C1), 110.9 (C2), 107.3 (C6), 99.9 (C4), 55.3 (OCH3); Analytical data is in agreement with literature [16c].
With boron tribromide; In hexane; dichloromethane; ethyl acetate;
Step C 3-Bromo-5-nitrophenol A solution of 3-bromo-5-nitroanisole, as described above in Step B, (2.4 g, 10.3 mmol) in methylene chloride (50 mL) was cooled to 0° C. and treated with boron tribromide (1M in CH2Cl2, 158 mL, 158 mmol), giving a clear purple solution. The reaction was warmed slowly to room temperature and stirred at room temperature overnight and heated at reflux for 2.5 hours. The reaction was poured into ice/water, the layers were separated and extracted with methylene chloride. The aqueous layer was neutralized with aqueous saturated NaHCO3 and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. This material was purified by column chromatography (10:1 to 5:1 hexane:ethyl acetate). The fractions containing the product contaminated with the bromoanisole were pooled, concentrated and purified using radial, thin layer chromatography (hexane to 5:1 hexane:ethyl acetate) to give 3-bromo-5-nitrophenol as a yellow solid. 1H NMR (delta, MeOH-d4): 7.81 (1H, m), 7.57 (1H, m), 7.32 (1H, m).
Example 34; BBr3 (8.62 mL of a 1.0 M solution in CH2Cl2; 8.62 mmol) was added to a solution of 1-bromo-3-methoxy-5-nitrobenzene (500 mg, 2.16 mmol) in CH2Cl2 (5 mL) at -20° C. The reaction was allowed to warm to RT and stirred at RT overnight, then was cautiously quenched with MeOH (30 mL) and stirred for 1 h at RT. Volatiles were removed in vacuo to give crude Part A Compound as a brown solid. 1H NMR (500 MHz, CDCl3) delta ppm 7.94 (s, 1 H), 7.62-7.64 (m, 1 H), 7.33 (s, 1 H), 5.84 (s, 1 H); LCMS Method A (ESI, positive ion spectrum): (M+H)/z=220, tR=3.14 min.
To a 0.70 M solution of l-bromo-3-methoxy-5-nitrobenzene (1.0 eq) in DCM was added a 1.0 M solution of boron tribromide in DCM (2.2 eq) while cooling in an ice/water bath. The reaction was stirred for 4 d at ambient temperature. The mixture was cooled to -78 C and quenched with methanol (15 eq). The mixture was returned to ambient temperature. Volatiles were removed under reduced pressure. The crude material was triturated with 5 : 1 watepimethanol (210 mL), filtered, and rinsed with additional solvent to give 31.9 g of the desired product as a lavender-grey solid after drying in a desiccator.
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In butan-1-ol; at 110℃; for 12.0h;Inert atmosphere;
3-(2-Methylpyridin-4-yl)-5-nitrobenzenamine (65.B). To a rt solution of65.A (available fromGLSynthesis Inc.) (5.00 g, 22.0 mmol) and 2-methylpyridin-4-ylboronic acid (available from CombiPhos Catalysts, Inc.) (2.71 g, 21.4mmol) in n-BuOH (38 rnL) was added potassium phosphate (available from Strem Chemicals, Inc.) (7.00 g, 33.0 mmol) and tris(dibenzylideneacetone)dipalladium (o) (available from Strem Chemicals, Inc.) (1.01 g, 1.2 mmol). After being purged with N2 for 15 mins, the mixture was stirred at 110 0C under N2 atmosphere for 12 hrs and resulting solution was concentrated. The residue was re-dissolved in EtOAc (60 mL), washed with water and brine, and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-9percent MeOH/ CH2Cl2 for elution gave the title product 65.B as yellow solid (4.8O g, 91percent).
With copper(l) iodide; L-proline; sodium hydroxide; In dimethyl sulfoxide; at 95℃; for 18h;
(i) 1 -(Cvclopropylsulfonyl)-3-methoxy-5-nitrobenzene A mixture of 1-bromo-3-methoxy-5-nitrobenzene (302 mg, 1.301 mmol), <strong>[910209-21-1]sodium cyclopropanesulfinate</strong> (200 mg, 1.561 mmol), Cu(l) iodide (25 mg, 0.131 mmol), L-proline (30.0 mg, 0.260 mmol) and NaOH (10.41 mg, 0.260 mmol) in DMSO (2 mL) was heated at 95C for 18h. The mixture was partitioned between EtOAc (50 mL) and water (50 mL), the organic layer separated, washed with water (50 mL), dried (MgS04) and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-40% EtOAc/isohexane) to afford the sub-title compound (135 mg) as a solid. 1 H NMR (400MHz; CDCI3) delta 8.31 (s, 1 H), 7.97 (s, 1 H), 7.72 (s, 1 H), 3.98 (s, 3H), 2.55- 2.48 (m, 1 H), 1.44-1.39 (m, 2H), 1.15-1.09 (m, 2H). LCMS m/z 258 (M+H)+ (ES+) weak ionisation
4.226 g
With copper(l) iodide; L-proline; sodium hydroxide; In dimethyl sulfoxide; at 90 - 100℃; for 30h;
A mixture of 1-bromo-3-methoxy-5-nitrobenzene (9.05 g, 39.0 mmol), <strong>[910209-21-1]sodium cyclopropanesulfinate</strong> (6.5 g, 50.7 mmol), copper(I) iodide (0.743 g, 3.90 mmol), L-proline (0.908 g, 7.88 mmol) and NaOH (0.315 g, 7.88 mmol) in DMSO (50 mL) was heated at 90 C. for 18 h and 100 C. for 12 h. The mixture was partitioned between EtOAc (500 mL) and water (300 mL), the organic layer separated, washed with brine (200 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-40% EtOAc/isohexane) to afford the sub-title compound (4.226 g) as a solid. 1H NMR (400 MHz; DMSO-d6) delta 8.31 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 3.98 (s, 3H), 2.55-2.49 (m, 1H), 1.48-1.36 (m, 2H), 1.15-1.10 (m, 2H).
4.226 g
With L-proline; sodium hydroxide; In dimethyl sulfoxide; at 90 - 100℃; for 30h;
A mixture of 1-bromo-3-methoxy-5-nitrobenzene (9.05 g, 39.0 mmol), sodiumcyclopropanesulfinate (6.5 g, 50.7 mmol), copper(l) iodide (0.743 g, 3.90 mmol), L-proline(0.908 g, 7.88 mmol) and NaOH (0.315 g, 7.88 mmol) in DMSO (50 mL) was heated at 90Cfor 18h and 100C for 12 h. The mixture was partitioned between EtOAc (500 mL) and water(300 mL), the organic layer separated, washed with brine (200 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-40% EtOAc/isohexane) to afford the sub-title compound (4.226 g) as a solid.1H NMR (400MHz; DMSO-d6) O 8.31 (5, 1H), 7.97 (5, 1H), 7.73 (5, 1H), 3.98 (5, 3H), 2.55-2.49 (m, 1H), 1.48-1.36 (m, 2H), 1.15-1.10 (m, 2H).
4.226 g
With copper(l) iodide; L-proline; sodium hydroxide; In dimethyl sulfoxide; at 90 - 100℃; for 30h;
(i) 1 -(Cyclopropylsulfonyl)-3-methoxy-5-nitrobenzeneA mixture of 1-bromo-3-methoxy-5-nitrobenzene (9.05 g, 39.0 mmol), sodiumcyclopropanesulfinate (6.5 g, 50.7 mmol), copper(l) iodide (0.743 g, 3.90 mmol), L-proline(0.908 g, 7.88 mmol) and NaOH (0.315 g, 7.88 mmol) in DMSO (50 mL) was heated at 90C for 18h and 100C for 12 h. The mixture was partitioned between EtOAc (500 mL) and water (300 mL), the organic layer separated, washed with brine (200 mL), dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified bychromatography on silica gel (120 g column, 0-40% EtOAc/isohexane) to afford the sub-titlecompound (4.226 g) as a solid.1H NMR (400MHz; DMSO-d6) O 8.31 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 3.98 (s, 3H), 2.55-2.49 (m, IH), 1.48-1.36 (m, 2H), 1.15-1.10 (m, 2H).
453 mg
With copper(l) iodide; L-proline; sodium hydroxide; In dimethyl sulfoxide; ethyl acetate; at 95℃; for 18h;
(i) A mixture of 1-bromo-3-methoxy-5-nitrobenzene (830 mg, 3.58 mmol), <strong>[910209-21-1]sodium cyclopropanesulfinate</strong> (550 mg, 4.29 mmol), copper(I) iodide (70 mg, 0.368 mmol), L-proline (82 mg, 0.715 mmol) and NaOH (29 mg, 0.725 mmol) in DMSO (5 mL) was heated at 95 C. for 18 h. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the organic layer separated, washed with water (100 mL), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc/isohexane) to afford the sub-title compound (453 mg) as a solid. 1H NMR (400 MHz; CDCl3) delta 8.30 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 3.99 (s, 3H), 2.54-2.47 (m, 1H), 1.44-1.39 (m, 2H), 1.13-1.07 (m, 2H).
433 mg
With copper(l) iodide; L-proline; sodium hydroxide; In dimethyl sulfoxide; at 95℃; for 18h;
(i) 1-(Cyclopropylsulfonyl)-3-methoxy-5-nitrobenzene A mixture of 1-bromo-3-methoxy-5-nitrobenzene (830 mg, 3.58 mmol), <strong>[910209-21-1]sodium cyclopropanesulfinate</strong> (550 mg, 4.29 mmol), copper(I) iodide (70 mg, 0.368 mmol), L-proline (82 mg, 0.715 mmol) and NaOH (29 mg, 0.725 mmol) in DMSO (5 mL) was heated at 95 C. for 18 h. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the organic layer separated, washed with water (100 mL), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc/isohexane) to afford the sub-title compound (453 mg) as a solid. 1H NMR (400 MHz; CDCl3) delta 8.30 (s, 1H), 7.95 (s, 1H), 7.74 (s, 1H), 3.99 (s, 3H), 2.54-2.47 (m, 1H), 1.44-1.39 (m, 2H), 1.13-1.07 (m, 2H).
Multi-step reaction with 2 steps
1.1: iron; ammonium chloride / tetrahydrofuran; water / 12 h / 55 °C
2.1: sulfuric acid / nitrobenzene / 3 h / 150 °C
2.2: 1 h / 25 °C
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere;
105a Synthesis of 105a
To a stirred solution of 98c (160 mg, 032 mmol, 1,0 equiv) and Pyridine (154 mg, 1.95 mmol, 6.0 equiv) in DCE (3 ml) was added tripliosgene (34mg. 0.11 tnmol, 0.35 equiv) at 0C under nitrogen atmosphere. The resulting mixture was stirred for 10 mm at room temperature under nitrogen atmosphere. The resulting mixture was washed with 3x10 m14 of sat. NaFICO3 (aq.) (10 ml). The resulting mixture was extracted with CH2Ch (3x10 mL). The combined organic layers were washed with water (3x1 0 mL) and dried over anhydrous CaCl2. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep..TLC (CH2CI2/MeOH=i0:i) to afford Compound 98 (61 mg, 35%) as a yellow solid.LC-MS: (ES, m/z): [M+HV 518H-NME.: (400 MHz, drnso-d6, S ppm): 1.19 (s, 6H), 2.97 (s, 3H), 3.53 (s, 2H), 3.71 (s, 2H), 4.66 (s, 1H), 4.9 1-4.96 (m, 4H), 6.87-6.89 (d, 1H), 6.98 (s, 1H), 7.23 (s, 1H), 7.37-7.42 (m, 3H), 7.75-7.77 (m, 1H), 8.20 (s, 1H).
98.72 %
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere;
105a Synthesis of 105a
To a stirred solution of 98c (160 mg, 032 mmol, 1,0 equiv) and Pyridine (154 mg, 1.95 mmol, 6.0 equiv) in DCE (3 ml) was added tripliosgene (34mg. 0.11 tnmol, 0.35 equiv) at 0C under nitrogen atmosphere. The resulting mixture was stirred for 10 mm at room temperature under nitrogen atmosphere. The resulting mixture was washed with 3x10 m14 of sat. NaFICO3 (aq.) (10 ml). The resulting mixture was extracted with CH2Ch (3x10 mL). The combined organic layers were washed with water (3x1 0 mL) and dried over anhydrous CaCl2. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep..TLC (CH2CI2/MeOH=i0:i) to afford Compound 98 (61 mg, 35%) as a yellow solid.LC-MS: (ES, m/z): [M+HV 518H-NME.: (400 MHz, drnso-d6, S ppm): 1.19 (s, 6H), 2.97 (s, 3H), 3.53 (s, 2H), 3.71 (s, 2H), 4.66 (s, 1H), 4.9 1-4.96 (m, 4H), 6.87-6.89 (d, 1H), 6.98 (s, 1H), 7.23 (s, 1H), 7.37-7.42 (m, 3H), 7.75-7.77 (m, 1H), 8.20 (s, 1H).
Chemistry
Pharmaceutical Intermediates
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