* 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 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium chloride In dimethyl sulfoxide at 160℃; for 24 h; Schlenk technique
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,39.4 mg of 2-nitro-5-methoxybenzoic acid and 17.5 mg of sodium chloride4 mL of dimethyl sulfoxide.The reaction was heated at 160 ° C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,25.1 mg of 2-nitro-5-methoxychlorobenzene was obtained,The yield is 67percent.
Reference：
[1] Tetrahedron Letters, 2010, vol. 51, # 50, p. 6646 - 6648
[2] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
[3] Patent: CN107325002, 2017, A, . Location in patent: Paragraph 0133
[4] Organic and Biomolecular Chemistry, 2018, vol. 16, # 30, p. 5416 - 5421
2
[ 611-06-3 ]
[ 124-41-4 ]
[ 28987-59-9 ]
Yield
Reaction Conditions
Operation in experiment
85.5%
at 68℃;
(2) in a machine equipped with mechanical stirring,Drip funnel and reflux condenser in a 500m 1 three-necked flask,Add 98g concentration of 98percentOf 2,4-dichloronitrobenzene and 200 g of anhydrous methanol,The 2,4-dichloronitrobenzene was dissolved in a methanol solution,At room temperature, 95 g of 30percentOf sodium methoxide solution,0.5 hours drop finished,The reaction was carried out at a reflux temperature of about 68 ° C for 5-6 hours,After the reaction,Methanol is distilled off at atmospheric pressure (can be recycled after methanol), Add water to salt,Stirring crystallization filtration,The product was recrystallized from 200 g of methanol (after steaming of the mother liquor,Methanol recycling),Filtered and dried to give 84.2 g2-chloro-4-methoxy nitrobenzene as pale yellow crystals,The measured content was 95.2percent and the yield was 85.5percent.
Reference：
[1] Patent: CN105859559, 2016, A, . Location in patent: Paragraph 0035
3
[ 2106-50-5 ]
[ 124-41-4 ]
[ 28987-59-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 20℃; for 1 h;
To a solution of 2-chloro-4-fluoro-1-nitrobenzene (220 mg, 1.253 mmol) in THF(2 mL) was added sodium methoxide (7.52 mL,0.5, 3.76 mmol). The mixture was stirredat room temperature for 1.0 h. LCMS indicated a completion of the reaction The mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified with flash chromatography (loading inchloroform, 0percent to 30percent EtOAc in hexanes over 12 mm using a 12 g silica gel cartridge).The desired fractions were combined and concentrated to give Intermediate 93A (230 mg,1.226 mmol, 98 percent yield) as a yellow liquid. ‘H NMR (400MHz, chloroform-d) 8.02 (d,J9.2 Hz, 1H), 7.03 (d, J2.6 Hz, 1H), 6.89 (dd, J=9.2, 2.6 Hz, 1H), 3.90 (s, 3H).LC-MS: method C, RT = 1.80 mm, MS (ESI) m/z: 188 (M+H)
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 20, p. 3797 - 3806
[2] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1998, vol. 340, # 6, p. 530 - 535
[3] Journal of the Chemical Society, 1926, p. 543[4] Journal of the Chemical Society, 1928, p. 628
[5] Patent: US5079257, 1992, A,
[6] Patent: WO2010/6086, 2010, A2, . Location in patent: Page/Page column 81-82
5
[ 615-58-7 ]
[ 28987-59-9 ]
Reference：
[1] Patent: US6476021, 2002, B1,
6
[ 40140-91-8 ]
[ 28987-59-9 ]
Reference：
[1] Journal of Organic Chemistry, 1985, vol. 50, # 20, p. 3797 - 3806
7
[ 108-43-0 ]
[ 28987-59-9 ]
Reference：
[1] Chemistry - A European Journal, 2002, vol. 8, # 9, p. 2034 - 2046
[2] Journal fuer Praktische Chemie/Chemiker-Zeitung, 1998, vol. 340, # 6, p. 530 - 535
8
[ 491-11-2 ]
[ 74-88-4 ]
[ 28987-59-9 ]
Reference：
[1] Indian Journal of Chemistry, 1965, vol. 3, p. 397 - 401
[2] Chemistry - A European Journal, 2002, vol. 8, # 9, p. 2034 - 2046
With ammonium chloride; zinc In methanol at 20℃; for 1 h;
To a solution of Intermediate 93A (230 mg, 1.226 mmol) in MeOH (6.0 mL) was added ammonium chloride (1312 mg, 24.52 mmol) and zinc dust (802 mg, 12.26 mmol).The mixture was stirred at room temperature for 1 h. MeOH was removed under vacuum. The residue was diluted with EtOAc/saturated sodium bicarbonate and stirred at room temperature for 10 mm. The mixture was filtered to remove insoluble material. The filtrate was collected, organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude sample was purified with a 12g ISCO column eluted with0-100percent EtOAc in hexanes for 15 mm. The desired fraction was collected and concentrated to give Intermediate 93B (193 mg, 1.225 mmol, 100 percent yield) as oil. ‘H NMR (400MHz, chloroform-d) 6.86 (t, J2.5 Hz, 1H), 6.76-6.64 (m, 2H), 3.74 (d, J3.1 Hz, 3 H). LC-MS: method C, RT = 0.8 mm, MS (ESI) m/z: 158 (M+H)
86%
With iron; ammonium chloride In methanol; water at 50℃; for 1 h;
Fe (5.10 g, 91.69 mmol) was added to a suspension of 2-chloro-4-methoxy-l-nitrobenzene (1.72 g, 9.17 mmol) and NH4CI (1.96 g, 36.68 mmol) in water (22mL) and MeOH (70 mL). The reaction mixture was warmed up to 50 °C and stirred at this temperature for 1 h. The mixture was cooled down to rt, filtered and rinsed with water (2x15 mL). The filtrate was extracted with EtOAc (2x50 mL); the combined organic layers were dried over Na2SO4 (anhydrous), filteredand concentrated. The crude residue was purified by flash chromatography on Si02 (l0—22percent EtOAc/hexanes), to give 2-chloro-4-methoxyaniline (orange oil, 1.24 g, 86percent yield).HPLC-MS (Method A): Ret, 7.37 mm; ESl-MS mlz: 158 (M+l).
Reference：
[1] Patent: WO2018/13774, 2018, A1, . Location in patent: Page/Page column 455
[2] Patent: WO2018/1973, 2018, A1, . Location in patent: Page/Page column 196
[3] Journal of the Chemical Society, 1927, p. 2218[4] Journal of the Chemical Society, 1928, p. 331
[5] Journal of the Chemical Society, 1927, p. 2218[6] Journal of the Chemical Society, 1928, p. 331
[7] Journal of the Chemical Society, 1926, p. 543[8] Journal of the Chemical Society, 1928, p. 628
[9] Chemistry - A European Journal, 2002, vol. 8, # 9, p. 2034 - 2046
12
[ 28987-59-9 ]
[ 491-11-2 ]
Yield
Reaction Conditions
Operation in experiment
90.5%
at 110℃; for 15 h;
(3) with mechanical agitation,Drip funnel and reflux condenser in a 500m 1 three-necked flask,Add 99g content95percent 2-chloro-4-methoxy nitrobenzene solid,350 g of 20percent K0H solution and 3 g of PEG400,Stirring heating,Reflex at 110 ° CShould be about 15 hours,After the solid is completely dissolved,Plus hydrochloric acid,Precipitation of 2-chloro-4-hydroxy nitrobenzene,After filtration drying,To give 82.5 g of 2-chloro-4-hydroxy nitrobenzene as a yellow solid,Measured content of 95.2percentThe yield was 90.5percent.
Reference：
[1] Patent: CN105859559, 2016, A, . Location in patent: Paragraph 0036
13
[ 28987-59-9 ]
[ 704-14-3 ]
Reference：
[1] Journal of the Chemical Society, 1929, p. 2778
14
[ 28987-59-9 ]
[ 6480-66-6 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 2218[2] Journal of the Chemical Society, 1928, p. 331
3-chloro-4-nitroanisole (4) In an atomosphere of N2 were added to a stirred suspension of 31 g NaH in 2.2 l anhydrous THF 199.5 g (1.15 mole) <strong>[491-11-2]3-chloro-4-nitrophenol</strong> (3). This was followed by the addition of dimethylsulfate (575 ml). The whole mixture was heated under reflux during 1.5 h. After cooling, it was poured into a cold (0 C.) diluted NH4 OH solution, to destroy the excess of dimethylsulfate, and stirred for two hours. The product was isolated by extraction with diethylether. The ethereal extracts were dried with MgSO4 and evaporated at reduced pressure affording 156 g (72.4%) of 3-chloro-4-nitroanisole. 1 H NMR delta(CDCl3); 8.07 (d, 1H, J=9.5 Hz, H-5), 7.05 (d, 1H, J=2.5 Hz, H-2), 6.99 (d.d, 1H, J=9.5 Hz, J=2.5 Hz, H-6), 3.92 (s, 3H, OCH3).
With potassium carbonate; In ethanol; for 2h;Reflux;
Synthesis of l-(tert-butoxycarbonyl) - 7 chloro- 5 methoxy-lH-indol-2-yl boronic acid is shown in Scheme 4. Meta- chlorophenol is nitrated with fuming nitric acid in acetic acid to yield 4- nitro-3- chlorophenol, compound 4-2. The phenol is methylated with dimethylsulfate and potassium carbonate in ethanol, producing compound 4-3, which is treated with vinyl Grignard reagent and cyclized to form the indole, compound 4- 4. Compound 4-4 is protected with Boc and then treated with lithium diispropylamide and triisopropylborate to produce the protected substituted boronic acid 4-6.
With ammonium chloride; zinc; In methanol; at 20℃; for 1h;
To a solution of Intermediate 93A (230 mg, 1.226 mmol) in MeOH (6.0 mL) was added ammonium chloride (1312 mg, 24.52 mmol) and zinc dust (802 mg, 12.26 mmol).The mixture was stirred at room temperature for 1 h. MeOH was removed under vacuum. The residue was diluted with EtOAc/saturated sodium bicarbonate and stirred at room temperature for 10 mm. The mixture was filtered to remove insoluble material. The filtrate was collected, organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude sample was purified with a 12g ISCO column eluted with0-100% EtOAc in hexanes for 15 mm. The desired fraction was collected and concentrated to give Intermediate 93B (193 mg, 1.225 mmol, 100 % yield) as oil. ?H NMR (400MHz, chloroform-d) 6.86 (t, J2.5 Hz, 1H), 6.76-6.64 (m, 2H), 3.74 (d, J3.1 Hz, 3 H). LC-MS: method C, RT = 0.8 mm, MS (ESI) m/z: 158 (M+H)
86%
With iron; ammonium chloride; In methanol; water; at 50℃; for 1h;
Fe (5.10 g, 91.69 mmol) was added to a suspension of 2-chloro-4-methoxy-l-nitrobenzene (1.72 g, 9.17 mmol) and NH4CI (1.96 g, 36.68 mmol) in water (22mL) and MeOH (70 mL). The reaction mixture was warmed up to 50 C and stirred at this temperature for 1 h. The mixture was cooled down to rt, filtered and rinsed with water (2x15 mL). The filtrate was extracted with EtOAc (2x50 mL); the combined organic layers were dried over Na2SO4 (anhydrous), filteredand concentrated. The crude residue was purified by flash chromatography on Si02 (l0-22% EtOAc/hexanes), to give 2-chloro-4-methoxyaniline (orange oil, 1.24 g, 86% yield).HPLC-MS (Method A): Ret, 7.37 mm; ESl-MS mlz: 158 (M+l).
Ethyl 5-methoxy-2-nitrophenylcyanoacetate (5) To a suspension of 44.2 g of NaH in DMF (870 ml) was added a solution of ethylcyanoacetate (197.7 g) in anhydrous DMF (162 ml). After the addition the reaction mixture was stirred for 10 minutes. Subsequently 156 g (0.83 mole) <strong>[28987-59-9]3-chloro-4-nitroanisole</strong> were added. The resulting dark solution was heated at 50-55 C. for 16 h. After cooling, the reaction mixture was poured into cold (0 C.) 5% KOH aq. The solution thus obtained was washed with ether (3*). Thereupon the solution was acidified with conc. 30% HCl aq., while cooling by adding crushed ice. During the acidification the colour of the mixture turned from dark red to pale yellow. From the collodial solution the product was isolated via an extraction with 1,1,1-trichloroethane (5*). The combined organic layers were dried with MgSO4. After evaporation of the solvent, a red oily residue was obtained, which was employed in the next step without further purification. Yield: 218.5 g (99.5%: contained only some DMF). Purification of a sample by flash column chromatography using silicagel and CH2 Cl2 as eluent afforded a pale yellow oil (yield: 95-100%) which crystallized on standing in the refrigerator. M.p. 44-47 C. IR(CHCl3): 2220 (C N), 1740 (ester C=O), 1580 (NO2). 1 H NMR delta(CDCl3): 8.28 (d, 1H, J=9 Hz, H-3), 7.27 (d, 1H, J=2.5 Hz, H-6), 7.04 (d.d, 1H, J=2.5 Hz and J=9 Hz, H-4), 5.68 (s, 1H, CHCNCO2 C2 H5), 4.33 (q, 2H, J=7 Hz CO2 CH2 CH3), 3.98 (s, 3H, OCH3), 1.33 (t, 3H, J=7 Hz CO2 CH2 CH3). An exact mass determination gave 264.0759; C12 H12 N2 O5 requires 264.0772 (4.9).
36.0%
EXAMPLE 37 - Synthesis of ethyl 2-cvano-2-(5-methoxy-2-nitrophenyl)acetate 15 (Scheme 5) Potassium tert-butoxide 15g (2 eq) was charged into an ice cold solution of ethyl cyanoacetate 18 g (17 mL, 2 eq)) in THF (200 mL) and was stirred for 15 min. To the white suspension, the compound 59 (1-chloro-5- methoxy-2-nitrobenzene) 15 g (1 eq) was added and the reaction mixture was heated to reflux for 24 h to 4 days. The cooled reaction mixture was poured into water and extracted into ether and the solvent was evaporated. The obtained compound crude ethyl 2-cyano-2-(5-methoxy-2-nitrophenyl)acetate MP-60 with starting material (7:3 ratio from TLC) was purified by flash column prior to using in next step. The solvent system was 3:7 chloroform/hexane. The eluent was EPO <DP n="74"/>changed to chloroform and 10% methanol after the complete starting material was recovered. The slow moving spot was the compound 15 confirmed from TLC. (Yield: 7.6 g; 36.0 % as dark yellow oil)
With potassium hydroxide; sodium hydroxide; In water;
<Step 1> Synthesis of 3-(2,4-dibromophenoxy)-4-nitroanisole 3-chloro-4-nitroanisole (7.0 g) prepared by the procedure described in J. Org. Chem., 17, 1475 (1952) and 2,4-dibromophenol (9.4 g) were melted at 120 to 125 C. under an argon atmosphere, followed by dropwise addition of 10N aqueous solution of potassium hydroxide (3.5 mL) over 2 hours. Then, the mixture was stirred at 140 to 145 C. for 3 hours and cooled to 100 C. Thereafter, 30% aqueous solution of sodium hydroxide (14 mL) and water (140 mL) were successively added. The mixture was allowed to cool and extracted with methylene chloride. The methylene chloride layer was washed with 1N aqueous solution of sodium hydroxide and dried over anhydrous sodium sulfate.
5,6-Dimethoxy-2-(5-methoxy-2-nitrophenylthio)-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide;
(a) 5,6-Dimethoxy-2-(5-methoxy-2-nitrophenylthio)-1H-benzimidazole 5,6-Dimethoxy benzimidazole-2-thione (4.0 g), <strong>[28987-59-9]2-chloro-4-methoxy nitrobenzene</strong> (3.6 g) and potassium carbonate (2.65 g) were stirred together in dry dimethyl formamide (30 ml) at 95 for 3 days. The cooled mixture was poured onto water (300 ml) and the precipitate collected. The solid was washed with water and dried to leave the sub-title compound as a pale yellow solid, MS 361 bp 207.
In methanol; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water;
(a) 2,4'-diamino-5-methoxydiphenylsulfide A warm solution of 3-chloro-4-nitro-1-methoxybenzene in 400 ml of methanol is added dropwise at 80 C. to a solution of 1 mol of p-aminothiophenol-Na in 200 ml of methanol and 400 ml of water. The reaction mixture is then stirred under reflux for 3 hours, cooled, diluted with 1 l of ice water, suction filtered, washed with water and dried. 1 mol of the nitroamino compound is dissolved in methanol and hydrogenated to the diamine with Raney nickel in known manner.
Synthesis of l-(tert-butoxycarbonyl) - 7 chloro- 5 methoxy-lH-indol-2-yl boronic acid is shown in Scheme 4. Meta- chlorophenol is nitrated with fuming nitric acid in acetic acid to yield 4- nitro-3- chlorophenol, compound 4-2. The phenol is methylated with dimethylsulfate and potassium carbonate in ethanol, producing compound 4-3, which is treated with vinyl Grignard reagent and cyclized to form the indole, compound 4- 4. Compound 4-4 is protected with Boc and then treated with lithium diispropylamide and triisopropylborate to produce the protected substituted boronic acid 4-6.
With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium chloride; In dimethyl sulfoxide; at 160℃; for 24h;Schlenk technique;
Silak reaction tube equipped with a magnetic stirrer was charged with 6.2 mg of silver sulfate,36.3 mg of copper acetate, 12.5 mg of 2,9-dimethyl-1,10-o-phenanthroline,39.4 mg of 2-nitro-5-methoxybenzoic acid and 17.5 mg of sodium chloride4 mL of dimethyl sulfoxide.The reaction was heated at 160 C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,25.1 mg of 2-nitro-5-methoxychlorobenzene was obtained,The yield is 67%.
(2) in a machine equipped with mechanical stirring,Drip funnel and reflux condenser in a 500m 1 three-necked flask,Add 98g concentration of 98%Of 2,4-dichloronitrobenzene and 200 g of anhydrous methanol,The 2,4-dichloronitrobenzene was dissolved in a methanol solution,At room temperature, 95 g of 30%Of sodium methoxide solution,0.5 hours drop finished,The reaction was carried out at a reflux temperature of about 68 C for 5-6 hours,After the reaction,Methanol is distilled off at atmospheric pressure (can be recycled after methanol), Add water to salt,Stirring crystallization filtration,The product was recrystallized from 200 g of methanol (after steaming of the mother liquor,Methanol recycling),Filtered and dried to give 84.2 g2-chloro-4-methoxy nitrobenzene as pale yellow crystals,The measured content was 95.2% and the yield was 85.5%.
(3) with mechanical agitation,Drip funnel and reflux condenser in a 500m 1 three-necked flask,Add 99g content95% 2-chloro-4-methoxy nitrobenzene solid,350 g of 20% K0H solution and 3 g of PEG400,Stirring heating,Reflex at 110 CShould be about 15 hours,After the solid is completely dissolved,Plus hydrochloric acid,Precipitation of 2-chloro-4-hydroxy nitrobenzene,After filtration drying,To give 82.5 g of 2-chloro-4-hydroxy nitrobenzene as a yellow solid,Measured content of 95.2%The yield was 90.5%.
trans-4-(tert-butoxycarbonylamino)cyclohexylamine[ No CAS ]
[ 28987-59-9 ]
tert-butyl [trans-4-(5-methoxy-2-nitroanilino)cyclohexyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With triethylamine; In acetonitrile; at 130℃; for 72h;Sealed tube;
A suspension of <strong>[28987-59-9]2-chloro-4-methoxy-1-nitrobenzene</strong> (2.0 g, 10.7 mmol), N-Boc-trans-1 ,4-cyclohexanediamine (2.3 g, 10.7 mmol) and triethylamine (1.8 mL, 12.8 mmol) in acetonitrile (80 mL) was heated at130C in a sealed tube for 3 days. The mixture was cooled to roomtemperature, the volatiles were removed under vacuum and the crudewas purified by column chromatography (from cyclohexane/EtOAc85:15 to cyclohexane/EtOAc/MeOH 6:3:1) to afford the title compound(1 .2 g, 3.3 mmol, 31% yield). LC-MS (M-H) = 366.4
To a solution of <strong>[2106-50-5]2-chloro-4-fluoro-1-nitrobenzene</strong> (220 mg, 1.253 mmol) in THF(2 mL) was added sodium methoxide (7.52 mL,0.5, 3.76 mmol). The mixture was stirredat room temperature for 1.0 h. LCMS indicated a completion of the reaction The mixture was diluted with EtOAc, quenched with saturated ammonium chloride. The organic layer was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified with flash chromatography (loading inchloroform, 0% to 30% EtOAc in hexanes over 12 mm using a 12 g silica gel cartridge).The desired fractions were combined and concentrated to give Intermediate 93A (230 mg,1.226 mmol, 98 % yield) as a yellow liquid. ?H NMR (400MHz, chloroform-d) 8.02 (d,J9.2 Hz, 1H), 7.03 (d, J2.6 Hz, 1H), 6.89 (dd, J=9.2, 2.6 Hz, 1H), 3.90 (s, 3H).LC-MS: method C, RT = 1.80 mm, MS (ESI) m/z: 188 (M+H)
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