* 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 iron; ammonium chloride In ethanol; water at 70℃; for 2 h;
N2-(4-chloro henyl)benzene-l,2-diamineTo a mixture of EtOH (100 ml) and NH4C1 saturated solution (15 ml),N-(4-chlorophenyl)-2-nitrobenzenamine (5.0 g, 20.1 mmol) was added, followed by iron powder (4.0 g). The reaction mixture was heated at 70 °C for 2h. The solid was filtered and the filtrate was extracted by EA (100 mL x 3), dried over Na2S04. After the solvent was removed, the mixture was purified by Combi-flash (PE : EA = 5 : 1) to giveN1-(4-chlorophenyl)benzene-l,2-diamine (4.1 g, 93.2 percent) as a light yellow solid. LRMS (M + H+) m/z calcd 218.06; found 218. 1H NMR (300 MHz, CD3OD): δ 6.52-6.59 (m, 3H), 6.70-6.74 (m, 1H), 6.81-6.87 (m, 1H), 6.90-6.99 (m, 3H).
92%
With hydrogen; nickel In N,N-dimethyl-formamide at 60 - 70℃;
In the hydrogenation reactor,100 g of N- (4-chlorophenyl) -2-nitro-1-aniline and 200 g of DMF were charged,After nitrogen replacement,Put 10 grams of nickel metal catalyst.Turn on stirringWarming to 60 degrees,Hydrogen gas to 3 kg pressure.Continuous access to hydrogen at 60 to 70 degrees,Until it no longer absorbs hydrogen,HPLC-controlled reaction process.When the condensate intermediate disappears,The reaction reached the end.Nitrogen replacement reaction system,Nickel catalyst was removed by hot filtration.The resulting filtrate was concentrated under reduced pressure to give about 100 g of DMF,Add 200 grams of deionized water,After slowly cooling to 20 degrees crystallization.The solid was isolated by filtration,After the solid was washed with appropriate amount of deionized water,Then cold toluene washing, drying.Finally, 81 g of crude N- (4-chlorophenyl) -1,2-phenylenediamine was obtained,Yield 92percentPurity greater than 98percentColor is gray brown.
Reference：
[1] Chinese Journal of Chemistry, 2013, vol. 31, # 12, p. 1473 - 1482
[2] Organic Process Research and Development, 2016, vol. 20, # 2, p. 452 - 464
[3] Patent: WO2012/151512, 2012, A2, . Location in patent: Page/Page column 103-104
[4] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 145 - 150
[5] Patent: CN107445845, 2017, A, . Location in patent: Paragraph 0047; 0048; 0049; 0050; 0051; 0052
[6] Chemische Berichte, 1902, vol. 35, p. 957 Anm.
[7] Liebigs Annalen, 1995, # 7, p. 1275 - 1282
[8] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 7, p. 1923 - 1926
[9] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 10, p. 3138 - 3141
[10] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 18, p. 5443 - 5448
[11] Patent: WO2012/3190, 2012, A1, . Location in patent: Page/Page column 45
[12] Molecules, 2012, vol. 17, # 4, p. 4545 - 4559
[13] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[14] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8409 - 8417,9
[15] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 1, p. 90 - 93
[16] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4475 - 4486
[17] Chinese Chemical Letters, 2017, vol. 28, # 8, p. 1731 - 1736
2
[ 106-47-8 ]
[ 68817-71-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 7, p. 1923 - 1926
[2] Chemische Berichte, 1902, vol. 35, p. 957 Anm.
[3] Molecules, 2012, vol. 17, # 4, p. 4545 - 4559
[4] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8409 - 8417,9
[6] Patent: WO2012/151512, 2012, A2,
[7] Chinese Journal of Chemistry, 2013, vol. 31, # 12, p. 1473 - 1482
[8] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 145 - 150
[9] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 1, p. 90 - 93
[10] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4475 - 4486
[11] Chinese Chemical Letters, 2017, vol. 28, # 8, p. 1731 - 1736
[12] Patent: WO2012/3190, 2012, A1,
3
[ 1493-27-2 ]
[ 68817-71-0 ]
Reference：
[1] Molecules, 2012, vol. 17, # 4, p. 4545 - 4559
[2] Chinese Chemical Letters, 2012, vol. 23, # 6, p. 707 - 710
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8409 - 8417,9
[4] Patent: WO2012/151512, 2012, A2,
[5] Chinese Journal of Chemistry, 2013, vol. 31, # 12, p. 1473 - 1482
[6] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 2, p. 145 - 150
[7] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 16, p. 4475 - 4486
[8] Patent: WO2012/3190, 2012, A1,
4
[ 88-73-3 ]
[ 68817-71-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 7, p. 1923 - 1926
[2] Chemische Berichte, 1902, vol. 35, p. 957 Anm.
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 1, p. 90 - 93
[4] Chinese Chemical Letters, 2017, vol. 28, # 8, p. 1731 - 1736
5
[ 106-47-8 ]
[ 1493-27-2 ]
[ 68817-71-0 ]
Reference：
[1] Organic Process Research and Development, 2016, vol. 20, # 2, p. 452 - 464
6
[ 99503-78-3 ]
[ 68817-71-0 ]
Reference：
[1] Chemische Berichte, 1902, vol. 35, p. 957 Anm.
7
[ 953-14-0 ]
[ 68817-71-0 ]
Reference：
[1] Chemische Berichte, 1902, vol. 35, p. 957 Anm.
EXAMPLE 17 1-(4-Chlorophenyl)-1,2-dihydro-3-phenylquinoxalin-2-one To a solution of N-(4-chlorophenyl)benzene-1,2-diamine (12.0 g) in a minimum quantity of ether was added benzoylformic acid (7.5 g) dissolved in ether and the mixture was stirred for 8 hours. The resulting precipitate was filtered, dried, and recrystallized from ethanol giving the title compound (11.0 g) mp 214.5-216.5 C. Analysis: 71.9%C; 4.2%H; 8.3%N; Requires: 72.2%C; 3.9%H; 8.4%N.
2-[3-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-propyl]-isoindole-1,3-dione[ No CAS ]
2-[4-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-butyl]-isoindole-1,3-dione[ No CAS ]
2-[5-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-pentyl]-isoindole-1,3-dione[ No CAS ]
2-[6-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-hexyl]-isoindole-1,3-dione[ No CAS ]
2-[3-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-propyl]-benzo[<i>de</i>]isoquinoline-1,3-dione[ No CAS ]
2-[4-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-butyl]-benzo[<i>de</i>]isoquinoline-1,3-dione[ No CAS ]
2-[5-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-pentyl]-benzo[<i>de</i>]isoquinoline-1,3-dione[ No CAS ]
2-[6-(4-{2-[10-(4-chloro-phenyl)-3-(4-chloro-phenylamino)-10<i>H</i>-phenazin-2-ylideneamino]-ethyl}-piperazin-1-yl)-hexyl]-benzo[<i>de</i>]isoquinoline-1,3-dione[ No CAS ]
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
EXAMPLE 11 Synthesis of 1-(4-chlorophenyl)-2-(4-chlorophenyl)-benzimidazole A solution of N-(4chlorophenyl)-1,2-phenylenediamine (2.19 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 4-chlorobenzoyl chloride (1.75 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH~14) was extracted with ethyl acetate (3*100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a crude red/brown solid. The reaction product was purified by trituration with diethyl ether to yield 2.91 grams (81.5%) of an off-white solid which was chromatographically homogeneous. mp 180-181 C. A solution of the intermediate prepared above (3.16 g, 8.8 mmol) in chloroform (90 ml) was stirred at room temperature as phosphorous oxychloride (1.36 g, 8.8 mmol) in chloroform (35 ml) was added dropwise. The reaction mixture was then refluxed overnight. The mixture was partitioned with 1N sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with chloroform (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.83 grams of a gray/brown solid. The reaction product was further purified by chromatography to yield 2.31 grams (77%) of a light pink solid. MS 339, 341, mp 162-164 C. Analysis for C19 H12 Cl2 N2: Theory: C, 67.27; H, 3.57; N, 8.30. Found: C, 67.45; H, 3.72; N, 8.36.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
EXAMPLE 11 Synthesis of 1-(4-chlorophenyl)-2-(4-chlorophenyl)-benzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.19 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 4-chlorobenzoyl chloride (1.75 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH~14) was extracted with ethyl acetate (3*100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a crude red/brown solid. The reaction product was purified by trituration with diethyl ether to yield 2.91 grams (81.5%) of an off-white solid which was chromatographically homogeneous. mp 180-181 C. A solution of the intermediate prepared above (3.16 g, 8.8 mmol) in chloroform (90 ml) was stirred at room temperature as phosphorous oxychloride (1.36 g, 8.8 mmol) in chloroform (35 ml) was added dropwise. The reaction mixture was then refluxed overnight. The mixture was partitioned with 1N sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with chloroform (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.83 grams of a gray/brown solid. The reaction product was further purified by chromatography to yield 2.31 grams (77%) of a light pink solid. MS 339, 341, mp 162-164 C. Analysis for C19 H12 Cl2 N2: Theory: C, 67.27; H, 3.57; N, 8.30. Found: C, 67.45; H, 3.72; N, 8.36.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
EXAMPLE 11 Synthesis of 1-(4-chlorophenyl)-2-(4-chlorophenyl)benzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.19 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 4-chlorobenzoyl chloride (1.75 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH~14) was extracted with ethyl acetate (3*100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a crude red/brown solid. The reaction product was purified by trituration with diethyl ether to yield 2.91 grams (81.5%) of an off-white solid which was chromatographically homogeneous. mp 180-181 C. A solution of the intermediate prepared above (3.16 g, 8.8 mmol) in chloroform (90 ml) was stirred at room temperature as phosphorous oxychloride (1.36 g, 8.8 mmol) in chloroform (35 ml) was added dropwise. The reaction mixture was then refluxed overnight. The mixture was partitioned with 1N sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with chloroform (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.83 grams of a gray/brown solid. The reaction product was further purified by chromatography to yield 2.31 grams (77%) of a light pink solid. MS 339, 341, mp 162-164 C. Analysis for C19 H12 Cl2 N2: Theory: C, 67.27; H, 3.57; N, 8.30. Found: C, 67.45; H, 3.72; N, 8.36.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
Example 11 Synthesis of 1-(4-chlorophenyl)-2-(4-chlorophenyl)-benzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.19 g, 10 mmol) in diethyl ether (85 ml) was stirred at room temperature as 4-chlorobenzoyl chloride (1.75 g, 10 mmol) in diethyl ether (35 ml) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH ~ 14) was extracted with ethyl acetate (3 x 100 ml). The organic fractions were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield a crude red/brown solid. The reaction product was purified by trituration with diethyl ether to yield 2.91 grams (81.5%) of an off-white solid which was chromatographically homogeneous. mp 180-181C. A solution of the intermediate prepared above (3.16 g, 8.8 mmol) in chloroform (90 ml) was stirred at room temperature as phosphorous oxychloride (1.36 g, 8.8 mmol) in chloroform (35 ml) was added dropwise. The reaction mixture was then refluxed overnight. The mixture was partitioned with 1N sodium hydroxide and the organic layer was removed. The aqueous fraction was extracted with chloroform (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.83 grams of a gray/brown solid. The reaction product was further purified by chromatography to yield 2.31 grams (77%) of a light pink solid. MS 339, 341, mp 162-164C.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform; ethyl acetate;
EXAMPLE 17 Synthesis of 1-(4-chlorophenyl)-2-(4-methoxyphenyl)-benzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.13 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as p-anisoyl chloride (1.71 g, 10 mmol) in diethyl ether (45 ml) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous fraction was extracted with ethyl acetate (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.6 grams of a brown/pink solid. The desired intermediate was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent to yield a light pink solid. mp 162-164 C. The intermediate prepared above (3.40 grams, 9.6 mmol) was dissolved in chloroform (90 ml). This solution was stirred at room temperature as phosphorous oxychloride in chloroform (40 ml) was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was partitioned with 1N sodium hydroxide and the organic layer removed. The aqueous fraction was further extracted with methylene chloride (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography to yield 2.64 grams (82.1%) of a light pink solid. MS 335, 337, mp 183-185 C. Analysis for C20 H15 ClN2 O: Theory: C, 71.75; H, 4.52; N, 8.37. Found: C, 71.67; H, 4.77; N, 8.59.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform; ethyl acetate;
EXAMPLE 17 Synthesis of 1-(4-chlorophenyl)-2-(4-methoxyphenyl)-benzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.13 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as p-anisoyl chloride (1.71 g, 10 mmol) in diethyl ether (45 ml) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The orgnaic layer was removed and the aqueous fraction was extracted with ethyl acetate (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.6 grams of a brown/pink solid. The desired intermediate was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent to yield a light pink solid. mp 162-164 C. The intermediate prepared above (3.40 grams, 9.6 mmol) was dissolved in chloroform (90 ml). This solution was stirred at room temperature as phosphorous oxychloride in chloroform (40 ml) was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was partitioned with 1N sodium hydroxide and the organic layer removed. The aqueous fraction was further extracted with methylene chloride (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography to yield 2.64 grams (82.1%) of a light pink solid. MS 335, 337, mp 183-185 C. Analysis for C20 H15 ClN2 O: Theory: C, 71.75; H, 4.52; N, 8.37. Found: C, 71.67; H, 4.77; N, 8.59.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform; ethyl acetate;
EXAMPLE 17 Synthesis of 1-(4-chlorophenyl)-2-(4-methoxyphenyl)benzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.13 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as p-anisoyl chloride (1.71 g, 10 mmol) in diethyl ether (45 ml) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The orgnaic layer was removed and the aqueous fraction was extracted with ethyl acetate (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.6 grams of a brown/pink solid. The desired intermediate was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent to yield a light pink solid. mp 162-164 C. The intermediate prepared above (3.40 grams, 9.6 mmol) was dissolved in chloroform (90 ml). This solution was stirred at room temperature as phosphorous oxychloride in chloroform (40 ml) was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was partitioned with 1N sodium hydroxide and the organic layer removed. The aqueous fraction was further extracted with methylene chloride (3*150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography to yield 2.64 grams (82.1%) of a light pink solid. MS 335, 337, mp 183-185 C. Analysis for C20 H15 ClN2 O: Theory: C, 71.75; H, 4.52; N, 8.37. Found: C, 71.67; H, 4.77; N, 8.59.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform; ethyl acetate;
Example 17 Synthesis of 1-(4-chlorophenyl)-2-(4-methoxyphenyl)benzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.13 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as p-anisoyl chloride (1.71 g, 10 mmol) in diethyl ether (45 ml) was added dropwise. The mixture was stirred overnight at room temperature. The reaction mixture was partitioned with 1N sodium hydroxide. The orgnaic layer was removed and the aqueous fraction was extracted with ethyl acetate (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 3.6 grams of a brown/pink solid. The desired intermediate was further purified by chromatography using a hexanes/ethyl acetate (3:1) solution as the eluent to yield a light pink solid. mp 162-164C. The intermediate prepared above (3.40 grams, 9.6 mmol) was dissolved in chloroform (90 ml). This solution was stirred at room temperature as phosphorous oxychloride in chloroform (40 ml) was added dropwise. The reaction mixture was refluxed overnight. The reaction mixture was partitioned with 1N sodium hydroxide and the organic layer removed. The aqueous fraction was further extracted with methylene chloride (3 x 150 ml). The organic layers were combined, washed with a saturated sodium chloride solution, dried over potassium carbonate, filtered, and the solvents were removed in vacuo. The reaction product was further purified by chromatography to yield 2.64 grams (82.1%) of a light pink solid. MS 335, 337, mp 183-185C.
1-(4-chlorophenyl)-2-phenyl-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
EXAMPLE 8 Synthesis of 1-(4-chlorophenyl)-2-phenylbenzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.19 g, 10 mmol) in diethyl ether (75 ml) was stirred at room temperature as benzoyl chloride (1.41 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. A precipitate quickly formed. The reaction mixture was stirred overnight and partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH~14) was extracted with ethyl acetate (3*150 ml). The organic layers were combined, washed with saturated sodium chloride, dried over potassium carbonate, filtered and removed in vacuo. The crude product was triturated in diethyl ether to yield 1.84 grams (57%) of a white solid which was chromatographically homogenous. mp 158-160 C. A solution of the intermediate prepared supra (0.33 g, 7.2 mmol) in chloroform (80 ml) was stirred at room temperature as phosphorous oxychloride (1.10 g, 7.2 mmol) in chloroform (30 ml) was added dropwise. After the addition was complete the reaction mixture was refluxed overnight. The reaction mixture was alkalinized to pH=14 with 1N sodium hydroxide and separated. The aqueous layer was extracted with chloroform (3*10 ml). The organic layers were combined, washed with a saturated sodium chloride, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.45 grams of a red/brown oil which solidified upon setting at room temperature.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
EXAMPLE 8 Synthesis of 1-(4-chlorophenyl)-2-phenylbenzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.19 g, 10 mmol) in diethyl ether (75 ml) was stirred at room temperature as benzoyl chloride (1.41 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. A precipitate quickly formed. The reaction mixture was stirred overnight and partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH~14) was extracted with ethyl acetate (3*150 ml). The organic layers were combined, washed with saturated sodium chloride, dried over potassium carbonate, filtered and removed in vacuo. The crude product was triturated in diethyl ether to yield 1.84 grams (57%) of a white solid which was chromatographically homogenous. mp 158-160 C. A solution of the intermediate prepared supra (.33 g, 7.2 mmol) in chloroform (80 ml) was stirred at room temperature as phosphorous oxychloride (1.10 g, 7.2 mmol) in chloroform (30 ml) was added dropwise. After the addition was complete the reaction mixture was refluxed overnight. The reaction mixture was alkalinized to pH=14 with 1N sodium hydroxide and separated. The aqueous layer was extracted with chloroform (3*10 ml). The organic layers were combined, washed with a saturated sodium chloride, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.45 grams of a red/brown oil which solidified upon setting at room temperature.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
EXAMPLE 8 Synthesis of 1-(4-chlorophenyl)-2-phenylbenzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.19 g, 10 mmol) in diethyl ether (75 ml) was stirred at room temperature as benzoyl chloride (1.41 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. A precipitate quickly formed. The reaction mixture was stirred overnight and partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH~14) was extracted with ethyl acetate (3*150 ml). The organic layers were combined, washed with saturated sodium chloride, dried over potassium carbonate, filtered and removed in vacuo. The crude product was triturated in diethyl ether to yield 1.84 grams (57%) of a white solid which was chromatographically homogenous. mp 158-160 C. A solution of the intermediate prepared supra (0.33 g, 7.2 mmol) in chloroform (80 ml) was stirred at room temperature as phosphorous oxychloride (1.10 g, 7.2 mmol) in chloroform (30 ml) was added dropwise. After the addition was complete the reaction mixture was refluxed overnight. The reaction mixture was alkalinized to pH=14 with 1N sodium hydroxide and separated. The aqueous layer was extracted with chloroform (3*10 ml). The organic layers were combined, washed with a saturated sodium chloride, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.45 grams of a red/brown oil which solidified upon setting at room temperature.
With sodium hydroxide; trichlorophosphate; In diethyl ether; chloroform;
Example 8 Synthesis of 1-(4-chlorophenyl)-2-phenylbenzimidazole A solution of <strong>[68817-71-0]N-(4-chlorophenyl)-1,2-phenylenediamine</strong> (2.19 g, 10 mmol) in diethyl ether (75 ml) was stirred at room temperature as benzoyl chloride (1.41 g, 10 mmol) in diethyl ether (30 ml) was added dropwise. A precipitate quickly formed. The reaction mixture was stirred overnight and partitioned with 1N sodium hydroxide. The organic layer was removed and the aqueous layer (pH ~ 14) was extracted with ethyl acetate (3 x 150 ml). The organic layers were combined, washed with saturated sodium chloride, dried over potassium carbonate, filtered and removed in vacuo. The crude product was triturated in diethyl ether to yield 1.84 grams (57%) of a white solid which was chromatographically homogenous. mp 158-160C. A solution of the intermediate prepared supra (.33 g, 7.2 mmol) in chloroform (80 ml) was stirred at room temperature as phosphorous oxychloride (1.10 g, 7.2 mmol) in chloroform (30 ml) was added dropwise. After the addition was complete the reaction mixture was refluxed overnight. The reaction mixture was alkalinized to pH = 14 with 1N sodium hydroxide and separated. The aqueous layer was extracted with chloroform (3 x 10 ml). The organic layers were combined, washed with a saturated sodium chloride, dried over potassium carbonate, filtered, and the solvents were removed in vacuo to yield 2.45 grams of a red/brown oil which solidified upon setting at room temperature.
1-(4-chlorophenyl)-1,2-dihydro-3-hydroxyquinoxalin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 1 1-(4-Chlorophenyl)-1,2-dihydro-3-hydroxyquinoxalin-2-one N-(4-Chlorophenyl)benzene-1,2-diamine (11.2 g) was added to diethyl oxalate (50 ml) and the mixture heated under reflux for 2 hours. The mixture was cooled and ethanol (40 ml) was added. The precipitated solid was filtered off and recrystallized from ethanol giving the title compound (11.2 g) mp>300 C.
With SULFAMIDE; In diethylene glycol dimethyl ether; for 0.5h;Heating / reflux;
Dry diglyme (10 mL) was added to a flask under a nitrogen atmosphere and brought to a vigorous reflux (oil bath maintained at 190 C.). A solution of N-(4-chloro-phenyl)-benzene-1,2-diamine (1.09 g, 5.0 mmol) and sulfamide (0.58 g, 6 mmol) in diglyme (5 mL) was added dropwise to the refluxing solution over 15 minutes. The mixture was refluxed an additional 15 minutes and then cooled and diluted with ether, washed with 2N HCl, water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was dissolved in ether and passed though a plug of silica gel to give 1-(3-bromopropyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.66 g, 47%). MS (ESI) m/z 279; HPLC purity 94.7% at 210-370 nm, 9.3 min.; Xterra RP18, 3.5 u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 minutes, hold 4 minutes.
47%
With SULFAMIDE; In diethylene glycol dimethyl ether; for 0.5h;Heating / reflux;
Step 1 : Dry diglyme (10 ml_) was added to a flask equipped with a dropping funnel under a nitrogen atmosphere and brought to a vigorous reflux. lambda/-(4-chloro-phenyl)- benzene-1 ,2-diamine (1.09 g, 5.0 mmol) and sulfamide (0.58 g, 6.0 mmol) were dissolved in 5 mL of diglyme and placed in the dropping funnel. The mixture was added dropwise to the flask over 15 minutes and then refluxing was continued for an additional 15 minutes. The mixture was cooled to ambient temperature and diluted with ether, washed with water, 2N HCI, water, brine, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified via lsco chromatography (Redisep, silica, gradient 5-50% (ethyl acetate containing 2% formic acid) in hexane) to afford 1-(4-chlorophenyl)-1 ,3-dihydro-2,1 ,3- benzothiadiazole 2,2-dioxide 0.66 g (47%). MS (ESI) m/z 279HPLC purity 94.7% at 210-370 nm, 9.3 minutes.; Xterra RP18, 3.5u, 150 x 4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 60℃;Combinatorial reaction / High throughput screening (HTS);
Step 2. Catalytic amination of the solid supported 8-iodo-l-methyl-4,5-dihydro- lH-pyrazolo [4,3-h] quinazoline-3-carboxamide; <n="82"/>Using a 4 niL Argonaut Trident synthesizer cassette, 200 mg (0.11 mmol) of the resin from step 1 above, were charged into separate vials. To each of the reactor vials flushed with argon, finely divided potassium carbonate (0.15 g, 1.1 mmol), palladium acetate [Pd(OAc)2] (2.5mg, 0.011 mmol, 10%), (HK)-BINAP (6.8 mg, 0.011 mmol, 10%) and the corresponding amine (0.22 mmol, 2 equivalents) in degassed (argon) dimethyacetamide (2 mL) were added. The resulting mixture was agitated at 600C for 10 hours on the Argonaut Trident Automated Library Synthesizer (ALS) station. The Trident ALS station was programmed to continuously mechanically agitate the resin at 6O0C while a nitrogen gas "sparge" was incorporated to re-suspend the scarcely soluble potassium carbonate. Nitrogen gas sparging was incorporated once per hour, for a 30 second duration, throughout the 16-hour heating cycle.The resin was drained from the synthesis cocktail and washed using the Argonaut Trident External Agitation Thermal Unit (EATU) synthesis station with DMA (3 x 2 mL, 5 min.). The above catalytic amination cycle was repeated a second time using the previously described procedure.Upon completion of the second amination cycle, the resin was drained from the synthesis cocktail and washed using the Argonaut Trident EATU synthesis station with DMF (1 x 2 mL, 5 min.), with water (1 x 2 mL, 5 min.), with DMF/water (1 : 1) (3 x 2 mL, 5 min.), with DMF (3 x 2 mL, 5 min.), with methanol (3 x 2 mL, 5 min.) and with DCM (3 x 2 mL, 5 min.).
With Pt-TiO2; at 32℃; for 4.0h;UV-irradiation; Inert atmosphere;
The photocatalytic and catalytic synthesis was carried out using the following procedure. Appropriate amounts of catalyst and 2-nitrodiphenylamine or 2-aminodiphenylamine in 25 mL of alcohol were taken in a reaction tube. The reaction tube was sealed with a rubber septum and purged with nitrogen for 30 min. The reaction mixture was irradiated with UV (365 nm) medium-pressure mercury lamp (Sankyo Denki, Japan; intensity I = 1.381 × 10-6 einstein L-1 s-1)/ solar light at constant stirring. The temperature of the reaction medium during UV irradiation was 32 C and it was nearly constant. With solar light, the temperature of the solution changed gradually from 32 to 48 C for all the experiments. The progress of the reaction was monitored using thin layer chromatography (TLC). Product analysis was performed by GC analysis, Perkin-Elmer GC-9000 with a capillary column of DB-5 and flame ionization detector was used. GC-MS analysis was carried out using Varian 2000 Thermo with the following features: capillary column VF5MS (5% phenyl-95% methylpolysiloxane), 30 m length, 0.25 mm internal diameter, 0.25 mum film thickness, temperature of column range from 50-280 C (10 C/min) and injector temperature 250 C, attached with mass spectrometer model SSQ 7000. The isolation was performed by column chromatography on a silica gel column by eluting with a co-solvent of dichloromethane and methanol (volume ratio: 8:2). For solar experiments, all reactions have been carried out under similar conditions on sunny days of different months of 2008-2009 between 10 A.M. and 2 P.M. The intensity of solar light was measured using a LT Lutron LX-10/A digital Lux meter and it was found to be 1250 × 100 (+/-100) lux. The intensity was nearly constant during the experiments.
1-(4-chlorophenyl)-2-methyl-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%Chromat.
With Pt-TiO2; at 32℃; for 4.0h;UV-irradiation; Inert atmosphere;
The photocatalytic and catalytic synthesis was carried out using the following procedure. Appropriate amounts of catalyst and 2-nitrodiphenylamine or 2-aminodiphenylamine in 25 mL of alcohol were taken in a reaction tube. The reaction tube was sealed with a rubber septum and purged with nitrogen for 30 min. The reaction mixture was irradiated with UV (365 nm) medium-pressure mercury lamp (Sankyo Denki, Japan; intensity I = 1.381 × 10-6 einstein L-1 s-1)/ solar light at constant stirring. The temperature of the reaction medium during UV irradiation was 32 C and it was nearly constant. With solar light, the temperature of the solution changed gradually from 32 to 48 C for all the experiments. The progress of the reaction was monitored using thin layer chromatography (TLC). Product analysis was performed by GC analysis, Perkin-Elmer GC-9000 with a capillary column of DB-5 and flame ionization detector was used. GC-MS analysis was carried out using Varian 2000 Thermo with the following features: capillary column VF5MS (5% phenyl-95% methylpolysiloxane), 30 m length, 0.25 mm internal diameter, 0.25 mum film thickness, temperature of column range from 50-280 C (10 C/min) and injector temperature 250 C, attached with mass spectrometer model SSQ 7000. The isolation was performed by column chromatography on a silica gel column by eluting with a co-solvent of dichloromethane and methanol (volume ratio: 8:2). For solar experiments, all reactions have been carried out under similar conditions on sunny days of different months of 2008-2009 between 10 A.M. and 2 P.M. The intensity of solar light was measured using a LT Lutron LX-10/A digital Lux meter and it was found to be 1250 × 100 (+/-100) lux. The intensity was nearly constant during the experiments.
With Pt-TiO2; at 32 - 48℃; for 4.0h;Solar light; Inert atmosphere;
The photocatalytic and catalytic synthesis was carried out using the following procedure. Appropriate amounts of catalyst and 2-nitrodiphenylamine or 2-aminodiphenylamine in 25 mL of alcohol were taken in a reaction tube. The reaction tube was sealed with a rubber septum and purged with nitrogen for 30 min. The reaction mixture was irradiated with UV (365 nm) medium-pressure mercury lamp (Sankyo Denki, Japan; intensity I = 1.381 × 10-6 einstein L-1 s-1)/ solar light at constant stirring. The temperature of the reaction medium during UV irradiation was 32 C and it was nearly constant. With solar light, the temperature of the solution changed gradually from 32 to 48 C for all the experiments. The progress of the reaction was monitored using thin layer chromatography (TLC). Product analysis was performed by GC analysis, Perkin-Elmer GC-9000 with a capillary column of DB-5 and flame ionization detector was used. GC-MS analysis was carried out using Varian 2000 Thermo with the following features: capillary column VF5MS (5% phenyl-95% methylpolysiloxane), 30 m length, 0.25 mm internal diameter, 0.25 mum film thickness, temperature of column range from 50-280 C (10 C/min) and injector temperature 250 C, attached with mass spectrometer model SSQ 7000. The isolation was performed by column chromatography on a silica gel column by eluting with a co-solvent of dichloromethane and methanol (volume ratio: 8:2). For solar experiments, all reactions have been carried out under similar conditions on sunny days of different months of 2008-2009 between 10 A.M. and 2 P.M. The intensity of solar light was measured using a LT Lutron LX-10/A digital Lux meter and it was found to be 1250 × 100 (+/-100) lux. The intensity was nearly constant during the experiments.
General procedure: General procedure: 1,5-Difluoro-2,4-dinitrobenzene (10.86 mmol) and TEA (10.94 mmol) were added to a solution of the proper N1-((4-substituted)phenyl)benzene-1,2-diamine (10.86 mmol) in 40 ml of ethanol. The mixture was stirred at rt for 1.5 h. The formed suspension was filtered and the resulting solid washed with ethanol. 4.4.2 N1-(4-Chlorophenyl)-N2-(5-fluoro-2,4-dinitrophenyl)benzene-1,2-diamine (31) Yield: 94%. Mp 211.7-214.0 C (lit. 36 209-211 C; lit. 22 216-217 C). 1H NMR (CDCl3) delta: 9.6 (br s, 1H, collapsed with D2O); 9.14 (d, 1H, J = 7.70 Hz); 7.36-7.21 (m, 5H); 7.10-7.04 (m, 1H); 6.97.6.93 (m, 2H); 6.67-6.63 (m, 1H); 5.63 (br s, 1H, collapsed with D2O).
With triethylamine; In methanol; at 20℃; for 4.0h;
The solid from step B was added to a solution of l ,3-difluoro-4,6-dinitrobenzene (46 g) in methanol (200 mL), then triethylamine (31.4 mL) was added, and stirred at rt for 4 h. The reaction mixture was filtered, and the cake was washed with methanol to give 80.6 g of red solid.
In toluene;Reflux;Product distribution / selectivity;
l-(4- hlorophenyl)-lH-benzo[b][l,4]diazepine-2,4(3H,5H)-dioneTo a stirred refluxing solution of N1-(4-chlorophenyl)benzene-l,2-diamine (100.0 mg, 0.46 mmol) in toluene (20 mL) was added dropwise a solution of malonyl dichloride (65.00 mg, 0.46 mmol). After addition was completed, the reaction mixture was refluxed for lh. The solvent was removed in vacuo, the mixture was stirred with water (20 mL), extracted with DCM (10 mL*3), and then was purified by Prep-TLC (DCM : MeOH = 30 : 1) to givel-(4-chlorophenyl)-lH-benzo[b][l,4]diazepine-2,4(3H,5H)-dione (80.00 mg, 60%) as a white solid. LRMS (M + H+) m/z calcd 286.05; found 286.
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