* 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.
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 6, p. 1239 - 1242
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 15, p. 7188 - 7211
[3] ACS Infectious Diseases, 2017, vol. 3, # 3, p. 225 - 236
[4] Australian Journal of Chemistry, 1982, vol. 35, # 4, p. 775 - 784
[5] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1900, vol. <5> 9 II, p. 271
[6] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 1691,1694; engl. Ausg. S. 1779, 1781
[7] Patent: US4314065, 1982, A,
[8] Patent: US4096263, 1978, A,
[9] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5010 - 5014
[10] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
[11] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8875 - 8894
2
[ 615-16-7 ]
[ 4857-06-1 ]
Reference：
[1] Synthetic Communications, 1996, vol. 26, # 17, p. 3323 - 3329
[2] Journal of Medicinal Chemistry, 1986, vol. 29, # 6, p. 1099 - 1113
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4508 - 4522
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 14, p. 6278 - 6293
[5] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 3, p. 707 - 718
[6] Patent: US5461059, 1995, A,
[7] Patent: US5149700, 1992, A,
[8] Patent: US6756382, 2004, B2,
[9] Patent: US2003/144283, 2003, A1,
3
[ 463-73-0 ]
[ 95-54-5 ]
[ 4857-06-1 ]
Reference：
[1] Journal of the Korean Chemical Society, 2010, vol. 54, # 5, p. 589 - 593
[2] Journal of the Chilean Chemical Society, 2012, vol. 57, # 2, p. 1122 - 1125,4
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 15, p. 7188 - 7211
[3] ACS Infectious Diseases, 2017, vol. 3, # 3, p. 225 - 236
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8875 - 8894
7
[ 134469-07-1 ]
[ 4857-06-1 ]
[ 615-16-7 ]
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 24, p. 9287 - 9291
8
[ 15108-18-6 ]
[ 4857-06-1 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1983, p. 217 - 220[2] Khimiya Geterotsiklicheskikh Soedinenii, 1983, vol. 19, # 2, p. 265 - 267
9
[ 1544-75-8 ]
[ 4857-06-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5010 - 5014
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1900, vol. <5> 9 II, p. 271
12
[ 64-17-5 ]
[ 4857-06-1 ]
[ 82299-33-0 ]
Reference：
[1] Russian Journal of Organic Chemistry, 2009, vol. 45, # 1, p. 135 - 138
13
[ 615-16-7 ]
[ 10026-13-8 ]
[ 10025-87-3 ]
[ 4857-06-1 ]
Reference：
[1] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1900, vol. <5> 9 II, p. 271
14
[ 4857-06-1 ]
[ 124-40-3 ]
[ 2851-13-0 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 200℃; for 0.5 h;
Commercially available 2-chloro-1H-benzo[d]imidazole (250 mg, 1.64 mmol) was dissolved in DMF (4.7 mL), dimethylamine (50percent aqueous solution, 0.50 mL, 4.92 mmol) was added, and the mixture was stirred with heating at 200°C for 30 min in an Emrys Optimizer microwave synthesizer. Water was added to the mixture, and the precipitated crystals were collected by suction filtration to give N,N-dimethyl-1H-benzo[d]imidazole-2-amine (234 mg, 89percent). ESIMS m/z: 162 (M + H)+; 1H NMR (270 MHz, DMSO-d6, δ): 3.03 (s, 6H), 6.79-6.97 (m, 2H), 7.07-7.20 (m, 2H), 11.17 (br s, 1H)
Reference：
[1] Patent: EP2740730, 2014, A1, . Location in patent: Paragraph 0320
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 1513 - 1522
15
[ 4857-06-1 ]
[ 68-12-2 ]
[ 2851-13-0 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 8, p. 4190 - 4195
16
[ 4857-06-1 ]
[ 60-34-4 ]
[ 2851-13-0 ]
Reference：
[1] Polyhedron, 2017, vol. 123, p. 243 - 251
17
[ 4857-06-1 ]
[ 506-59-2 ]
[ 2851-13-0 ]
Reference：
[1] Zhurnal Obshchei Khimii, 1953, vol. 23, p. 1691,1694; engl. Ausg. S. 1779, 1781
18
[ 4857-06-1 ]
[ 15108-18-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 14, p. 6278 - 6293
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5885 - 5895
[3] Chemistry - A European Journal, 2011, vol. 17, # 5, p. 1473 - 1484
[4] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
19
[ 4857-06-1 ]
[ 615-36-1 ]
[ 28890-99-5 ]
Reference：
[1] Patent: WO2017/17096, 2017, A1,
20
[ 4857-06-1 ]
[ 74-96-4 ]
[ 58533-15-6 ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h; Stage #2: at 20℃;
General procedure: 2-Chloro-1H-benzoimidazole (3.04 g, 20 mmol) was dissolved in dry DMF (15 mL) at 0 °C, to the solution was added NaH (0.91 g, 22.7 mmol), and the mixture was stirred for 1 h at 0 °C, then halide (21.6 mmol) was added. The mixture was stirred overnight at room temperature and was poured into water (50 mL) and stirred for 1 h, filtrated, washed with water and dried to afford 4a-d.
Reference：
[1] Zeitschrift fur Anorganische und Allgemeine Chemie, 2013, vol. 639, # 14, p. 2450 - 2454
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 417 - 422
[3] European Journal of Medicinal Chemistry, 2010, vol. 45, # 3, p. 909 - 914
21
[ 4857-06-1 ]
[ 75-03-6 ]
[ 58533-15-6 ]
Yield
Reaction Conditions
Operation in experiment
61%
With NaH In N,N-dimethyl-formamide; mineral oil
Step 1) Preparation of 2-Chloro-1-ethylbenzimidazole To a cooled (0° C.) stirred suspension of NaH (60percent dispersion in mineral oil; 7.08 g, 0.118 mol) in DMF (100 mL) was added 2-chlorobenzimidazole (15.00 g, 0.098 mol). The mixture was warmed to room temperature and stirred for 1 hour. Ethyl iodide (18.40 g, 0.118 mol) was added and stirring was continued for 3 hours. The mixture was poured onto the ice water and the resulting off-white solid was collected by filtration to give 10.0 g (61percent) of product m.p. 48°-50° C. NMR (DMSO-d6, 300 MHz): δ1.3 (t, J=8.6 Hz, 3H), 4.28 (q, J=8.6 Hz, 2H), 7.25 (m, 2H), 7.60 (m, 2H).
Reference：
[1] Patent: US5149700, 1992, A,
[2] Patent: KR2018/36412, 2018, A, . Location in patent: Paragraph 0103; 0107-0108
22
[ 4857-06-1 ]
[ 64-67-5 ]
[ 58533-15-6 ]
Reference：
[1] Asian Journal of Chemistry, 2012, vol. 24, # 12, p. 5756 - 5758,3
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 9, p. 1210 - 1213
23
[ 4857-06-1 ]
[ 623-81-4 ]
[ 58533-15-6 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 6, p. 829 - 832
24
[ 4857-06-1 ]
[ 123324-71-0 ]
[ 49671-76-3 ]
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 34, p. 12877 - 12885
[2] ACS Catalysis, 2015, vol. 5, # 6, p. 3680 - 3688
25
[ 4857-06-1 ]
[ 74-89-5 ]
[ 17228-38-5 ]
Yield
Reaction Conditions
Operation in experiment
51%
at 160℃; for 16 h; Autoclave
The N-methyl-1H-benzo[d]imidazol-2-amine, used as starting material, can be prepared as follows:2-Chloro-1H-benzo[d]imidazole (20 g, 131.08 mmol) was charged to high pressure autoclave PV10832 (Hastelloy 450 ml) with methylamine (260 mL, 131.08 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 11 bar. The solvent was removed under reduced pressure to afford a brown oil. EtOH was added and the solvent again removed to afford a brown foam. The foam was dissolved in a minimum of hot acetone. This was then allowed to cool. The resultant solid was filtered affording N-methyl-1H-benzo[d]imidazol-2-amine (9.91 g, 51percent); 1H NMR (400 MHz, DMSO-d6) 2.83 (3H, s), 6.87-7.00 (2H, m), 7.05-7.25 (2H, m), 7.49 (1H, s).
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 41, p. 10364 - 10367
[2] Tetrahedron Letters, 2016, vol. 57, # 9, p. 1035 - 1039
[3] Patent: US2011/306613, 2011, A1, . Location in patent: Page/Page column 29
[4] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1985, p. 1513 - 1522
26
[ 4857-06-1 ]
[ 459-46-1 ]
[ 84946-20-3 ]
Yield
Reaction Conditions
Operation in experiment
91.1%
Stage #1: With potassium hydroxide In acetonitrile at 80℃; for 0.5 h; Stage #2: at 80℃; for 5 h;
To a solution of 2-chlorobenzomethylene (5 g, 32.7 mmol) was added 30 ml of acetonitrile and potassium hydroxide (2.62 g, 46.6 mmol) Heated to 80 ° C, stirred for 30min, the solution clarified; after cooling to room temperature, adding bromine bromide (9.29g, 49.1 mmol) 80 ° C reflux 5h, the reaction solution was white turbid; the reaction solution with dichloromethane extraction three times (100mLX3), distilled water The organic layers were combined, dried over anhydrous magnesium sulfate, suction filtered and concentrated to give a white solid which was recrystallized from acetone / petroleum ether and cooled And filtered, dried to give a white solid in a yield of 91.1percent.
Reference：
[1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 3, p. 245 - 249
[2] Patent: CN104910894, 2017, B, . Location in patent: Paragraph 0032; 0034; 0036; 0037; 0055
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 25, p. 6291 - 6294
[4] Heterocycles, 1999, vol. 51, # 11, p. 2561 - 2573
[5] Patent: US5922737, 1999, A,
[6] Patent: US6211199, 2001, B1,
[7] European Journal of Medicinal Chemistry, 2014, vol. 84, p. 395 - 403
[8] European Journal of Medicinal Chemistry, 2014, vol. 84, # C, p. 395 - 403
27
[ 4857-06-1 ]
[ 352-11-4 ]
[ 84946-20-3 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2016, vol. 53, # 6, p. 1871 - 1877
[2] Synthetic Communications, 1996, vol. 26, # 17, p. 3323 - 3329
[3] Patent: US5461059, 1995, A,
[4] Patent: US4695575, 1987, A,
28
[ 4857-06-1 ]
[ 7191-70-0 ]
[ 84946-20-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 24, p. 6332 - 6344
29
[ 4857-06-1 ]
[ 24424-99-5 ]
[ 214147-60-1 ]
Reference：
[1] Patent: EP1219622, 2002, A2, . Location in patent: Page 22
[2] Journal of Organic Chemistry, 2016, vol. 81, # 11, p. 4890 - 4897
[3] Patent: US6372736, 2002, B1,
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5010 - 5014
[5] Patent: WO2005/42518, 2005, A2, . Location in patent: Page/Page column 105; 107
In water; N,N-dimethyl-formamide; at 200℃; for 0.5h;
Commercially available 2-chloro-1H-benzo[d]imidazole (250 mg, 1.64 mmol) was dissolved in DMF (4.7 mL), dimethylamine (50% aqueous solution, 0.50 mL, 4.92 mmol) was added, and the mixture was stirred with heating at 200C for 30 min in an Emrys Optimizer microwave synthesizer. Water was added to the mixture, and the precipitated crystals were collected by suction filtration to give N,N-dimethyl-1H-benzo[d]imidazole-2-amine (234 mg, 89%). ESIMS m/z: 162 (M + H)+; 1H NMR (270 MHz, DMSO-d6, delta): 3.03 (s, 6H), 6.79-6.97 (m, 2H), 7.07-7.20 (m, 2H), 11.17 (br s, 1H)
The N-methyl-1H-benzo[d]imidazol-2-amine, used as starting material, can be prepared as follows:2-Chloro-1H-benzo[d]imidazole (20 g, 131.08 mmol) was charged to high pressure autoclave PV10832 (Hastelloy 450 ml) with methylamine (260 mL, 131.08 mmol) and sealed on its trolley and the resulting solution heated to 160 C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 11 bar. The solvent was removed under reduced pressure to afford a brown oil. EtOH was added and the solvent again removed to afford a brown foam. The foam was dissolved in a minimum of hot acetone. This was then allowed to cool. The resultant solid was filtered affording N-methyl-1H-benzo[d]imidazol-2-amine (9.91 g, 51%); 1H NMR (400 MHz, DMSO-d6) 2.83 (3H, s), 6.87-7.00 (2H, m), 7.05-7.25 (2H, m), 7.49 (1H, s).
Sodium hydride (purity 55%)(516 mg, 12.0 mmol) was added to a N,N-dimethylformamide solution (8.0 ml) of 2-chloro-1H-benzimidazole (1.52 g, 10.0 mmol), at 0C, under nitrogen stream, and stirring was carried out for 20 minutes. Methyl iodide (0.750 ml, 12.0 mmol) was further added, and stirring was carried out under room temperature for 2 hours. Water was added to the reaction solution, and the resulting solid substance was collected by filtration to afford 2-chloro-1-methyl-1H-benzimidazole (1.51 g, yield 91%) as a white solid.
88%
Step 1: 1.00 g, 6.5 mmol of 2-chlorobenzimidazole,Dissolved in 15 mL of tetrahydrofuran,Add 288mg, 7.2mmol 60% sodium hydride,After stirring for half an hour, 0.60 mL, 9.8 mmol of methyl iodide was added.The mixture was stirred at room temperature for 2 hours.Then add water, extract with ethyl acetate, wash with water, wash with brine, dry, concentrate, and then purify by column chromatography.1-Methyl-2-chlorobenzimidazole was obtained, a pale yellow liquid, 0.95 g, yield 88%.
85%
(2) Synthesis of intermediate (C-2); [0080][Chem. 12] Intermediate (C-2); [0081] 2-Chloro-benzimidazole (20 g (131 mmol, trade name: 2-Chlorobenzimidazole, manufactured by Aldrich) and THF (150 mL) were placed in a 500-mL three-neck flask, and t-butoxy sodium (13.8 g (144 mmol)) was added thereto under ice cooling. The mixture was stirred at room temperature for 1 hour. Subsequently, a solution of methyl iodide (24.2 g (170 mmol)) and THF (30 mL) was dropped into the flask under ice cooling, and the resulting mixture was stirred at room temperature for 5 hours. The reaction solution wasextracted with chloroform, followed by drying over anhydrous sodium sulfate. Subsequently, the solvent was removed to obtain 18.6 g (yield: 85%) of an intermediate (C-2) (2- chloro-1 -methyl- lH-benzimidazole, white crystal) .
79%
Step l1.5 g (9.8 mmol, 1 eq) of 2-chlorobenzoimidazole was dissolved in 10 ml of DMF in a dried round flask provided with nitrogen gas, 0.47 g (11.8 mmol, 1.2 eq) of sodium hydride was slowly added thereto at 0 C , and the mixture was incubated at room temperature for 1 hr. 1.7 g (11.8 mmol, 1.2 eq) of iodomethane was added thereto, followed by allowing the reaction mixture to react for 1 hr. After adding cold water thereto, the resulting solid was filtered, washed with ethyl acetate, and dried to obtain 1.3 g of 2-chloro-l-methylbenzoimidazole (yield: 79%).
67.9%
Example 275A 2-chloro-1-methyl-1H-benzo[d]imidazole To a solution of 2-chloro-1H-benzo[d]imidazole (2.0 g, 13.1 mmol) in DMF (10 mL) was added NaH (0.63 g, 15.7 mmol) at 0 C. under N2. After stirring for 30 min at 0 C., iodomethane (5.58 g, 39.3 mmol) was added and the mixture was stirred at room temperature for additional 1 hour. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with EtOAc (3*20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound (1.9 mg, 8.9 mmol, 67.9% yield) as a white solid. MS: MS (M+H)+; 1H NMR (400 MHz, CDCl3): delta 7.71-7.68 (m, 1H), 7.31-7.27 (m, 3H), 3.79 (s, 3H).
67.9%
2-chloro- 1 -methyl- 1 H-benzo [d] imidazole[670] To a solution of 2-chloro- lH-benzo[d]imidazole (2.0 g, 13.1 mmol) in DMF(10 mL) was added NaH (0.63 g, 15.7 mmol) at 0 C under N2. After stirring for 30 min at 0 C, iodomethane (5.58 g, 39.3 mmol) was added and the mixture was stirred at room temperature for additional 1 hour. The reaction mixture was quenched with water (100 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over a2S04, filtered, and concentrated to give the title compound (1.9 mg, 8.9 mmol, 67.9 % yield) as a white solid. MS: MS (M+H)+; XH NMR (400 MHz, CDC13): ? 7.71-7.68 (m, 1H), 7.31-7.27 (m, 3H), 3.79 (s, 3H).
65%
[0267] To a solution of 2-chloro-1H-benzo[d]imidazole (916 mg, 6 mmol) in 10 mL of dry DMF, which was cooled to 0 C., was careffilly added NaH (240 mg, 10.8 mmol) in small portions. The mixture was stirred for 15 minutes at this temperature. Then, methyl iodide (0.41 mL, 6.6 mmol) was added under continuous stirring for an additional 15 minutes. When thin layer chromatography (TLC) showed full conversion, the mixture was poured into 60 mL of water and a white solid precipitated. The precipitate was collected by filtration and dried in vacuo to obtain 2a 650 mg (65%) of pure product as a white solid. ?H NMR (400 MHz, DMSOd 5) oe 7.62-7.54 (m, 2H), 7.34-7.27 (m, 1H), 7.27-7.20 (m, 1H), 3.80 (s, 3H)
61%
2-Chloro-1H-benzimidazole (7.5 g, 49 mmol) was dissolved in dimethylformamide (20 mL),and the reaction mixture was cooled to oo C. Sodium hydride ( 60% dispersion in mineral oil 2.16 g,5 5.4 mmol) was carefully added. The reaction mixture was stirred at ambient temperature for 1 hour,and after that iodomethane (8.37g, 59 mmol) was added. The reaction mixture was stirred at ambienttemperature overnight, and then water (200 mL) was added. The solid was collected by filtration toafford 5 g, 61% of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) o ppm 3.79(s, 3H), 7.21-7.33 (m, 2H), 7.58 (t, J=7.0 Hz, 2H).
60.38%
With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 1h;
[1372] mel (6.1 ml, 98.3 mmol) was added to a mixture of 2-chloro-1H-benzo[d]imidazole (5.0 g, 32.8 mmol) and K2CO3 (13.6 g, 98.3 mmol) in DMF(20 ml). The mixture was stirred at 25 C for lh. The insoluble substance was removed by filtration and the filtrate was treated with ea (50 ml), H2O (50 ml). The organic layer was separated and the aqueous layer was extracted with ea (35 ml x 3). The combined organic layer was washed with H2O (35 ml x 2), brine (35 ml x 2), dried over mgs04, filtered and concentrated. The residue was triturated with tbme/pe (v/v = 1/1, -20 ml) to afford compound 294a (3.3 g, yield 60.38%) as pale yellow solid. 1H NMR (DMSO-d6, 400 mhz) delta .60 - 7.56 (m, 2h), 7.31 - 7.24 (m, 2h), 3.80 (s, 3h). MS (ESI) m/z (M+H)+ 167.0.
53%
General procedure: 2-Chloro-1H-benzoimidazole (3.04 g, 20 mmol) was dissolved in dry DMF (15 mL) at 0 C, to the solution was added NaH (0.91 g, 22.7 mmol), and the mixture was stirred for 1 h at 0 C, then halide (21.6 mmol) was added. The mixture was stirred overnight at room temperature and was poured into water (50 mL) and stirred for 1 h, filtrated, washed with water and dried to afford 4a-d.
In water; N,N-dimethyl-formamide;
(1) Sodium hydride (contained by 60%, 0.288 g) was suspended in DMF (10 mL), and 2-chlorobenzimidazole (1 g) was added thereto. The mixture was stirred at room temperature for 30 min and methyl iodide (0.61 mL) was added thereto. After stirring at room temperature for 1 hr, water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine and concentrated under reduced pressure to give 2-chloro-1-methylbenzimidazole (0.928 g) as a white powder.
Example 1N-(4-Fluoro-3-trifluoromethyl-benzyl)-N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide (Compound No.15)Step A: 2-Chloro-1-methyl-1H-benzimidazoleTo a solution of 2-chloro-1H-benzimidazole (5.03 g, 33.0 mmol) in anhydrous DMF (33 mL) at 0 C. was added portion-wise 95% NaH (871 mg, 36.3 mmol). The ice bath was removed and the resulting mixture was stirred at room temperature for 1 h. Iodomethane (4.68 g, 33.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with water, and the resulting precipitate was collected by filtration and purified by recrystallization from hexane to yield 2-chloro-1-methyl-1H-benzimidazole. MS 167 (M+1)+
2-Chloro-5-nitrobenzimidazole (19) To 210 mL of fuming HNO3, 2-chlorobenzimidazole (13.42 g, 87.95 mmole) was added portionwise over a period of 10 min with stirring and ice-H2 O cooling. After the addition, the cooling bath was removed and stirring was continued at room temperature overnight. This reaction mixture was cooled to ~0 C., poured into 300 mL of ice, and neutralized carefully with conc. NH4 OH to ~pH 8. The resulting suspension was filtered. The yellowish solid product was washed with portions of H2 O and air-dried. The filtrate and washings were combined and extracted with EtOAc (200 mL*2). The EtOAc solution was washed with sat. NaCl solution (200 mL*2), dried (Na2 SO4), and evaporated to give 1.3 g of a yellowish solid. The solid was combined with the major part of the product and was recrystallized from MeOH to give 16.34 g (5 crops, 94%) of 19 as yellowish crystals. mp 235-237
16.34 g (5 crops, 94%)
With nitric acid;
2-Chloro-5-nitrobenzimidazole (19) To 210 mL of fuming HNO3, 2-chlorobenzimidazole (13.42 g, 87.95 mmole) was added portionwise over a period of 10 min with stirring and ice-H2 O cooling. After the addition, the cooling bath was removed and stirring was continued at room temperature overnight. This reaction mixture was cooled to ~ 0 C., poured into 300 mL of ice, and neutralized carefully with conc. NH4 OH to ~ pH 8. The resulting suspension was filtered. The yellowish solid product was washed with portions of H2 O and air-dried. The filtrate and washings were combined and extracted with EtOAc (200 mL*2). The EtOAc solution was washed with sat. NaCl solution (200 mL*2), dried (Na2 SO4), and evaporated to give 1.3 g of a yellowish solid. The solid was combined with the major part of the product and was recrystallized from MeOH to give 16.34 g (5 crops, 94%) of 19 as yellowish crystals. mp 235-237 C. MS (EI) m/e 196.9984 (100%, M+ =196.9992). 1 H NMR (DMSO-d6) d 14.06 (br. s, 1, 1-NH), 8.41 (s, 1, 4-H), 8.14 (dd, 1, 6-H, J6-4 =2.0 Hz, J6-7 =9.0 Hz), 7.71 (d, 1, 7-H).
Example 84; Synthesis of lH-indazole-6-carboxylic acid [2-(2-isopropylphenylamino)-3H-benzimidazol- 5-yl]-amideTo a solution of 2-chloro-5-nitro-lH-benzimidazole (1.5 mmol; prepared from nitration of 2-chloro-lH-benzimidazole; GaIy et al, J. Heterocycl. Chem. 1997, 34, 6, 1781- 1788) in dry NMP (3 mL) was added 2-isopropylaniline (4 mmol). The resulting solution was subjected to microwave irradiation at 150 0C for Ih. The contents were cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (2x15 mL). The combined extracts were then washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue obtained was purified by silica gel chromatography using EtOAc/hexane as eluent to obtain (2- isopropylphenyl)-(5-nitro-lH-benzimidazol-2-yl)-amine as light yellow solid.The nitro compound (1 mmol) as above was reduced under hydrogenation conditions as described in general procedure F to afford lambda/"2-(2-isopropylphenyl)-lH-benzimidazole-2,5- diamine. Methyl Indazole-6-carboxylate (4 mmol; Batt el al, J. Med. Chem. 2000, 43, 41-58) was hydrolyzed as in general procedure C to obtain leta-Indazole-6-carboxylic acid. The <n="70"/>carboxylic acid (0.5 tnmol) was coupled with aforementioned N -(2-isopropylphenyl)-l H- benzimidazole-2,5-diamine (0.5 mmol) using HBTU as described in general procedure D to yield lH-indazole-6-carboxylic acid [2-(2-isopropylphenylamino)-3H-benzimidazol-5-yl]- amide as an off-white solid. MS: m/z 411 (M+H) .
With sulfuric acid; nitric acid; at 0℃; for 1h;
To a solution of 2-chloro-1 H-benzo[d]imidazole (10 g) in sulfuric acid (62.9 mL) at 0 C was slowly added dropwise nitric acid (17.57 mL). After 1 h, the reaction mixture was poured into ice water (100 mL). A yellow solid precipitated and was filtered and dried in vacuo to afford the title product (6.5 g). This was used directly in the next step.
General procedure: 2-Chloro-1H-benzoimidazole (3.04 g, 20 mmol) was dissolved in dry DMF (15 mL) at 0 C, to the solution was added NaH (0.91 g, 22.7 mmol), and the mixture was stirred for 1 h at 0 C, then halide (21.6 mmol) was added. The mixture was stirred overnight at room temperature and was poured into water (50 mL) and stirred for 1 h, filtrated, washed with water and dried to afford 4a-d.
88%
In a round bottom flask fitted with amagnetic stirrer, 2-chloro-1H-benzimidazole, 3, (0.50 g, 3.3 mmol) was dissolved in DMSO (3mL) and then NaH (60%; 0.19 g, 4.9 mmol) was added at 0 C and stirred for 1h. Next, benzylbromide (0.67 g, 3.9 mmol) was added to the suspension and the reaction was stirred at rt for 12h. Ice-cold water (15 mL) was added to the mixture and resulting precipitate was collected viafiltration. The filtrate was washed with water and dried under vacuum to give desired product, 4,as a white solid (0.75 g, 88%). LCMS: RT = 2.69 min., >98% 215 and 254 nm, m/z = 243.0 [M+ H]+. 1H NMR (499 MHz, CDCl3) δ 7.68 (d, J = 7.4 Hz, 1H), 7.35 - 7.24 (m, 5H), 7.16 (d, J =6.8 Hz, 2H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 141.33, 134.83, 128.99, 128.22, 126.76,123.53, 123.05, 119.18, 109.98, 47.94.
85%
Step 1: 1.00 g, 6.5 mmol of 2-chlorobenzimidazole, dissolved in 15 mL of tetrahydrofuran, added 174 mg, 12.1 mmol of 60% sodium hydride, stirred for half an hour, then added 1.2 mL, 10.1 mmol of benzyl bromide, and the mixture was stirred at room temperature. After 2 hours, water was added, ethyl acetate was extracted, washed with water, saturated with brine, dried, concentrated, and then purified by column chromatography to give 1-benzyl-2-chlorobenzimidazole, 1.34 g of pale yellow liquid. The rate is 85%.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: To a stirred solution of 1c (1.0 eq.) and POCl3 (10 eq.) was addeda few drops of conc. HCl. The reaction mixture was heated to 150 C and stirred for 3 h. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with 1 N aq. NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to givecrude product 1d. Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
Step B: 2-chloro 1-(4 fluorobenzyl) benzimidazole 11 g 2-chlorobenzimidazole are dissolved in 74 ml water and 17.35 ml 30% sodium hydroxide. The mixture is heated to 82 C. and to this they are slowly added 23.76 g 4-fluorobenzyl chloride within 5 hours. When the reaction is achieved, the solution is cooled to 20 C. and extracted with methylene chloride. The compound is recrystallized from ethyl acetate.
With potassium iodide; sodium carbonate; In chloroform; N,N-dimethyl-formamide;
EXAMPLE 8 A mixture of 60 parts of 2-chloro-1H-benzimidazole, 58 parts of 1-(chloromethyl)-4-fluorobenzene, 42.5 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70 C. The reaction mixture was poured into water. The precipitated product was filtered off and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 62.5 parts of 2-chloro-1-(4-fluorophenylmethyl)-1H-benzimidazole (61).
Dimethyl sulfate (11.0 mL, 116 mmol) was added to a solution of 2-chlorobenzimidazole (10.6 g, 70 mmol) in 2.5 M NaOH (70 mL, 175 mmol), and the mixture was stirred at 23 C. for 2 h. The reaction mixture was filtered, and the solid product was washed with H2O (6×50 mL) and dried in vacuo to afford a light brown solid (9.4 g, 81% yield). MS (ESI): mass calculated for C8H7ClN2, 166.03; m/z found, 167.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.75-7.70 (m, 1H), 7.35-7.29 (m, 3H), 3.82 (s, 3H).
81%
With sodium hydroxide; In water; at 23℃; for 2h;
EXAMPLE 8; 2-Chloro-1-methyl-1 H-benzoimidazole; Dimethyl sulfate (11.0 mL, 116 MMOL) was added to a solution of 2- chlorobenzimidazole (10. 6 g, 70 MMOL) in 2.5 M NAOH (70 mL, 175 MMOL), and the mixture was stirred at 23 C for 2 h. The reaction mixture was filtered, and the solid product was washed with H20 (6 x 50 mL) and dried in vacuo to afford a light brown solid (9. 4 g, 81 % yield). MS (ESI) : mass calculated for C8H7CIN2, 166.03 ; m/z found, 167.0 [M+H] +. 1H NMR (400 MHz, CDCI3) : 7.75- 7.70 (m, 1 H), 7.35-7. 29 (m, 3H), 3.82 (s, 3H)
81%
With sodium hydroxide; at 20℃; for 2h;
2-Chlorobenzimidazole (10 g, 65.56 mmol) was dissolved in 80 ml of 2.5 N NaOH (175 mmol) and dimethyl sulfate (11.0 ml, 116 mmol) was added drop wise under stirring at room temperature. After the addition the mixture was stirred for further 2h and the precipitate formed was filtered by suction and the product washed several times with ice-water mixture till the filtered solution was neutral. Petrol ether was sucked through the solid product several times and then dried in vacuo to afford a light brown solid (8.76 g, 81 % yield). 1HNMR (delta ppm): 3,78 (s, 3H, CH3), 7,26 (dq J=1.2Hz, J=7.4Hz, BZI-H5/H6), 7,54-7,60 (m, 2H, BZI-H4/H7).
81%
With sodium hydroxide; at 20℃; for 2h;
2-Chlorobenzimidazole (10 g, 65.56 mmol)was dissolved in 80 ml of 2.5N NaOH (175 mM) and dimethyl sulfate (11.0 mL, 116 mM) wasadded drop wise under stirring at room temperature. After the addition the mixture was stirredfor further 2 h and the precipitate formed was filtered by suction and the product washed severaltimes with ice-water mixture till the filtered solution was neutral. Petrol ether was suckedthrough the solid product several times and then dried in vacuo to afford a light brown solid(8.76 g, 81% yield). 1H NMR (200 MHz, d6-DMSO, delta): 3.78 (s, 3H, CH3), 7.26 (dq, J = 1.2Hz,J = 7.4Hz, BZI-H5/H6), 7.54-7.60 (m, 2H, BZI-H4/H7).
With sodium hydroxide; In water; at 0 - 20℃; for 2h;
a.) 2-Chloro-l-methyl-lH-benzimidazol; (GaIy J-P. Et al.: J. Het. Chem. 1997, 34, 6, 1781-88)To the solution of 3 g (20 mmol) 2-chlorobenzimidazole in 30 ml water under cooling on ice-bath 9 ml 5 N sodium hydroxide solution and then 3.3 ml (34.7 mmol) dimethyl sulfate is added. The reaction mixture is stirred at room temperature for 2 hours, the precipitated crystals are filtered off, washed with water and dried to obtain 2.8 g title compound. Mp: 115-1170C.
With sodium hydroxide; at 0℃; for 1.5h;
To a solution of 2-chloro-1H-benzo[d]imidazole (3.0019 g, 19.67 mmol, Sigma-Aldrich Chemical Company, Inc.) in 2.5 M sodium hydroxide solution (19.67 ml, 49.2 mmol, J. T. Baker) at 0 C. was added dimethyl sulfate (3.01 ml, 31.5 mmol, Riedel de Haen AG) dropwise. The reaction was allowed to stir for 1½ h. White precipitate was noted to form. The white precipitate was filtered, washed with water, and dried to give the title compound. LCMS showed product peak at 1.47 min (m+1=167.0). 1H NMR (400 MHz, DMSO-d6) delta ppm 3.80 (s, 3H) 7.21-7.28 (m, 1H) 7.28-7.35 (m, 1H) 7.59 (d, J=3.72 Hz, 1H) 7.61 (d, J=3.72 Hz, 1H)
To a solution of 2-chlorobenzomethylene (5 g, 32.7 mmol) was added 30 ml of acetonitrile and potassium hydroxide (2.62 g, 46.6 mmol) Heated to 80 C, stirred for 30min, the solution clarified; after cooling to room temperature, adding bromine bromide (9.29g, 49.1 mmol) 80 C reflux 5h, the reaction solution was white turbid; the reaction solution with dichloromethane extraction three times (100mLX3), distilled water The organic layers were combined, dried over anhydrous magnesium sulfate, suction filtered and concentrated to give a white solid which was recrystallized from acetone / petroleum ether and cooled And filtered, dried to give a white solid in a yield of 91.1%.
With sodium hydroxide; In N-methyl-acetamide; hexane; dichloromethane; water;
PREPARATION 2 (1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine Combine 2-chloro-1H-benzimidazole (17.75 g, 116 mmol) and 4-fluorobenzyl bromide (26.6 g, 141 mmol) in dimethylformamide (100 mL). Add a solution of sodium hydroxide (50 g) in water (75 mL). (Caution, exothermic). After 30 minutes, pour the reaction mixture into water (1800 mL) and stir to form a solid. After 1 hour, collect the solid by filtration, dissolve the solid in dichloromethane, and extract with water. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on a short column of silica gel eluding with 5% ethyl acetate/dichloromethane to give a solid. Recrystallize from chloroform/hexane to give, after drying, 1-(4-fluorobenzyl)-2-chloro-1H-benzimidazole.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: To a stirred solution of 1c (1.0 eq.) and POCl3 (10 eq.) was addeda few drops of conc. HCl. The reaction mixture was heated to 150 C and stirred for 3 h. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with 1 N aq. NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to givecrude product 1d. Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
General procedure: In a round bottom flask fitted with amagnetic stirrer, 2-chloro-1H-benzimidazole, 3, (0.50 g, 3.3 mmol) was dissolved in DMSO (3mL) and then NaH (60%; 0.19 g, 4.9 mmol) was added at 0 C and stirred for 1h. Next, benzylbromide (0.67 g, 3.9 mmol) was added to the suspension and the reaction was stirred at rt for 12h. Ice-cold water (15 mL) was added to the mixture and resulting precipitate was collected viafiltration. The filtrate was washed with water and dried under vacuum to give desired product, 4,as a white solid (0.75 g, 88%). LCMS: RT = 2.69 min., >98% 215 and 254 nm, m/z = 243.0 [M+ H]+. 1H NMR (499 MHz, CDCl3) delta 7.68 (d, J = 7.4 Hz, 1H), 7.35 - 7.24 (m, 5H), 7.16 (d, J =6.8 Hz, 2H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) delta 141.33, 134.83, 128.99, 128.22, 126.76,123.53, 123.05, 119.18, 109.98, 47.94.
With sodium hydroxide; In N-methyl-acetamide; hexane; dichloromethane; water;
PREPARATION 5 Synthesis of (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine Combine 2-chloro-1H-benzimidazole (17.75 g, 116 mmol) and 4-fluorobenzyl bromide (26.6 g, 141 mmol) in dimethylformamide (100 mL). Add a solution of sodium hydroxide (50 g) in water (75 mL). (Caution, exothermic). After 30 minutes, pour the reaction mixture into water (1800 mL) and stir to form a solid. After 1 hour, collect the solid by filtration, dissolve the solid in dichloromethane, and extract with water. Dry the organic layer over Na2 SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on a short column of silica gel eluding with 5% ethyl acetate/dichloromethane to give a solid. Recrystallize from chloroform/hexane to give, after drying, 1-(4-fluorobenzyl)-2-chloro-1H-benzimidazole.
Step 1 60% Sodium hydride (1.42 g, 35.4 mmol) was added to mixture of 2-chlorobenzimidazole (5 g, 32.8 mmol) and DMF (50 mL) under ice-cooling, stirred at room temperature for 30 minutes, then added to <strong>[622-95-7]4-chlorobenzyl bromide</strong> (7.61 g, 37 mmol), and then stirred overnight at room temperature. The reaction mixture was added to saturated chloride ammonium aqueous solution (200 mL), and extracted with ethyl acetate (30 mL*3). The organic phase was washed by 1 mol/L hydrochloride (30 mL), saturated sodium hydrogen carbonate aqueous solution (30 mL), and saturated saline (30 mL), dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The residue was purified by silica-gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-2-chlorobenzimidazole (7.45 g, yield: 82%) as pale yellow solid. 1H-NMR (delta ppm TMS/CDCl3): 5.36 (2H, s), 7.11 (2H, d, J=8.2 Hz), 7.20-7.31 (5H, m), 7.72 (1H, d, J=7.8 Hz).
General procedure: In a round bottom flask fitted with amagnetic stirrer, 2-chloro-1H-benzimidazole, 3, (0.50 g, 3.3 mmol) was dissolved in DMSO (3mL) and then NaH (60%; 0.19 g, 4.9 mmol) was added at 0 C and stirred for 1h. Next, benzylbromide (0.67 g, 3.9 mmol) was added to the suspension and the reaction was stirred at rt for 12h. Ice-cold water (15 mL) was added to the mixture and resulting precipitate was collected viafiltration. The filtrate was washed with water and dried under vacuum to give desired product, 4,as a white solid (0.75 g, 88%). LCMS: RT = 2.69 min., >98% 215 and 254 nm, m/z = 243.0 [M+ H]+. 1H NMR (499 MHz, CDCl3) delta 7.68 (d, J = 7.4 Hz, 1H), 7.35 - 7.24 (m, 5H), 7.16 (d, J =6.8 Hz, 2H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) delta 141.33, 134.83, 128.99, 128.22, 126.76,123.53, 123.05, 119.18, 109.98, 47.94.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 120℃; for 3h;Inert atmosphere;
Step3: Under nitrogen protection,2-Chlorobenzimidazole (1.41 g, 9.2 mmol) was added to the reaction vessel.Phenylboronic acid (1.02 g, 8.4 mmol),Tetrakistriphenylphosphine palladium (0.09g, 0.08mmol),Potassium carbonate (3.48g, 25.2mmol),Toluene 60mL, ethanol 20mL and distilled water 20mL,Stir at 120 ° C for 3 h.After the end of the reaction, the reaction was quenched with distilled water, ethyl acetate was extracted, and the organic layer was dried over MgSO..The solvent was removed by distillation under reduced pressure.After purification by silica gel column chromatography, Intermediate 75-3 (1.22 g, 75percent) was obtained.
75%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 120℃; for 3h;Inert atmosphere;
Step 3: Under the protection of nitrogen, 2-chlorobenzimidazole (1.41 g, 9.2 mmol) and phenylboronic acid were added to the reaction vessel. (1.02 g, 8.4 mmol), tetrakistriphenylphosphine palladium (0.09 g, 0.08 mmol), potassium carbonate (3.48 g, 25.2 mmol), toluene 60 mL, ethanol 20 mL, and distilled water 20 mL, and stirred at 120 ° C for 3 h. After the end of the reaction, the reaction was quenched with distilled water, extracted with ethyl acetate, and the organic layer was dried over MgSO 4 After purification by silica gel column chromatography, Intermediate 73-3 (1.22 g, 75percent).
75%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 120℃; for 3h;Inert atmosphere;
Under nitrogen protection,2-Chlorobenzimidazole (1.41 g, 9.2 mmol) was added to the reaction vessel.Phenylboronic acid (1.02 g, 8.4 mmol),Tetrakistriphenylphosphine palladium (0.09g, 0.08mmol),Potassium carbonate (3.48g, 25.2mmol),Toluene 60mL, ethanol 20mL and distilled water 20mL,Stir at 120 ° C for 3 h.After the reaction is over, the distilled water stops the reaction.Extracted with ethyl acetate,The organic layer was dried over MgSO 4The solvent was removed by distillation under reduced pressure.After purification by silica gel column chromatography, Intermediate 7-7 (1.22 g, 75percent) was obtained.
75%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 120℃; for 3h;Inert atmosphere;
Step3: Under nitrogen protection,Add to the reaction vessel2-chlorobenzimidazole (1.41 g, 9.2 mmol),Phenylboronic acid (1.02 g, 8.4 mmol),Tetrakistriphenylphosphine palladium (0.09g, 0.08mmol),Potassium carbonate (3.48g, 25.2mmol),Toluene 60mL,20mL of ethanol and 20mL of distilled water,Stir at 120 ° C for 3 h.After the reaction is over, the distilled water stops the reaction.Extracted with ethyl acetate,The organic layer was dried over MgSO 4The solvent was removed by distillation under reduced pressure.After purification by silica gel column chromatography, Intermediate 77-3 (1.22 g, 75percent).
Preparation 46 tert-Butyl 2-chloro-1H-1,3-benzimidazole-1-carboxylate 2-Chloro-1H-1,3-benzimidazole (1.07 g) was added to a solution of di-tert-butyldicarbonate (1.83 g) and 4-dimethylaminopyridine (86 mg) in acetonitrile (15 ml). The reaction mixture was stirred at room temperature for 30 minutes, after which time the solvent was removed under reduced pressure. The crude product was then purified by column chromatography on silica gel eluding with a solvent gradient of 100:0 changing to 90:10, by volume, hexane:ethyl acetate to afford tert-butyl 2-chloro-1H-1,3-benzimidazole-1-carboxylate (1.68 g) as a white solid. 1H-NMR (CDCl3) delta: 7.90 (1H, m), 7.35 (1H, m), 7.40 (2H, m), 1.80 (9H, s). MS: 253 (MH+).
With triethylamine; In isopropyl alcohol; at 20℃; for 19.0h;Product distribution / selectivity;
Example 1. 4- (2- ( (2, 6-Dimethylphenyl) oxy)-1H-benzimidazol-1-yl)-N- (4- (4- methyl-l-piperazinyl) phenyl)-2-pyrimidinamine; Step A: 2-Chloro-benzoimidazole-l-carboxylic acid tert-butyl ester; Di-tert-butyldicarbonate (12.270 g, 56.221 mmol) was added to a solution of 2- chlorobenzimidazole (8. 41 g, 55.119 mmol) and triethylamine (20 mL) in isopropanol (90 mL). The reaction mixture was stirred at room temperature for 19 h and then concentrated. The resulting material was purified via column chromatography on silica gel (eluting with dichloromethane) to afford 2-chloro- benzoimidazole-1-carboxylic acid tert-butyl ester as a white solid.
A mixture of 2-chloro-1H-benzimidazole (0.0189 mol) and 1,1-dimethylethyl 2-aminocyclohexanecarbamoate (0.04725 mol) (prepared according to A1a))was stirred at 140C for 3 hours, then brought to room temperature and taken up in CH2Cl2/CH3OH. The same procedure was repeated 3 times on the same quantities of 2-chloro-1H-benzimidazole and 1,1-dimethylethyl 2-aminocyclohexanecarbamoate. The mother layers were brought together, dried (MgSO4), filtered and the solvent was evaporated. The residue (28g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/ NH4OH 96/4/0.1; 15-35mum). Two fractions were collected and the solvent was evaporated, yielding 4.5g of intermediate (84) (24%).
cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate;
A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g). Data for (J): 1H NMR (300 MHz, CDCl3) delta 7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q, 2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22 (t, 3 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate;
A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g). Data for (J): 1H NMR (300 MHz, CDCl3) delta7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q, 2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22 (t, 3 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate;
A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure a tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g) Data for (J): 1H NMR (300 MHz, CDCl3) delta 7.28 (br s, 2H), 7.02 (m, 2H), 5.16 (br s, 1H), 4.15 (q, 2H), 3.97 (br s, 1H), 2.40 (br s, 1H), 1.80-1.54 (m, 8H), 1.22 (t, 3H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester[ No CAS ]
trans 4-(1H-benzirnidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate;
A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzirnidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g). Data for (J): 1H NMR (300 MHz, CDCl3) delta 7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q, 2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22 (t, 3 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
PREPARATION 1.2 Synthesis of 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) and dimethylformamide (200 mL). Add portionwise, sodium hydride (24.0 g, 60% in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl ethyl ether (21.9 g, 201,5 mmol). Heat to 60 C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluding sequentially with 10% ethyl acetate/hexane and then 30% ethyl acetate hexane to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: Rf =0.74 (silica gel, 7/3 ethyl acetate/hexane).
In N-methyl-acetamide; ethyl acetate;
Preparation 1.2 4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) and dimethylformamide (200 mL). Add portionwise, sodium hydride (24.0 g, 60% in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl ethyl ether (21.9 g, 201,5 mmol). Heat to 60 C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluding sequentially with 10% ethyl acetate/hexane and then 30% ethyl acetate hexane to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: Rf=0.74 (silica gel, 7/3 ethyl acetate/hexane).
EXAMPLE 2 2-Chloro-1-(1-methylethyl)-1H-benzimidazole. 13.5 g (0.0885 mole) of 2-chloro-1H-benzimidazole, 9.2 ml of 1-bromo-1-methylethyl, 230 g of potassium carbonate and 200 ml of dimethyl sulphoxide are introduced into a round-bottom flask. The mixture is vigorously stirred for 4 hours while maintaining the temperature at 60 C. It is extracted several times with ether. The organic phases are combined and concentrated. The pasty residue is purified on a silica gel column eluding with a mixture of ethyl acetate and hexane in proportions of 20:80 v/v. The pure fractions are concentrated under vacuum. The residue is dissolved in 20 ml of hexane with the use of heat. The solution is cooled on a ice bath, the crystals are drained and then washed with a small amount of hexane and dried under vacuum. 12 g of compound are obtained. Melting point: 62 C.
In N-methyl-acetamide; water; N,N-dimethyl-formamide;
A. 1-Benzyl-2-chlorobenzimidazole A solution of 2-chlorobenzimidazole (100 g, 0.65 mol) in 500 ml of dimethylformamide (DMF) was added dropwise to a stirred suspension of 60% sodium hydride-mineral oil dispersion (28 g, 0.70 mol) in 500 ml of DMF. Mild intermittent cooling was required. After the addition was completed the mixture was stirred an additional 15 min and benzylbromide (82.6 g, 0.49 mol) was added dropwise with mild intermittent cooling. The reaction mixture was stirred an additional 1.5 h and 1 L of water was added. The mixture was extracted with benzene. The extract was dried (Na2 SO4), concentrated and the residue crystallized from isopropyl ether to obtain 110 g (93%), mp 102-105 C.
With NaH; methyl iodide; In N,N-dimethyl-formamide; mineral oil;
Step 2) Preparation of 2-Chloro-1-methylbenzimidazole According to the procedure D. Harrison, et al., J. Chem. Soc., 2930, 1963, to a cooled (5 C.), stirred solution of 2-chlorobenzimidazole (26.1 g, 0.171 mol) in DMF (125 mL) was added NaH (60% dispersion in mineral oil; 7.2 g, 0.180 mol) in several portions. After 30 minutes MeI (25.5 g, 0.180 mol) was added. The cooling bath was removed and stirring was continued for 30 minutes. The mixture was recooled, H2 O (200 mL) was added, and the resulting precipitate was collected by filtration to give 20.2 g (71%) of product as an off-white solid m.p. 107-109 C. NMR (DMSO-d6, 300 MHz): delta3.78 (s, 3H), 7.20-7.33 (m, 2H), 7.58 (m, 2H).
Step 1) Preparation of 2-Chloro-1-ethylbenzimidazole To a cooled (0 C.) stirred suspension of NaH (60% dispersion in mineral oil; 7.08 g, 0.118 mol) in DMF (100 mL) was added 2-chlorobenzimidazole (15.00 g, 0.098 mol). The mixture was warmed to room temperature and stirred for 1 hour. Ethyl iodide (18.40 g, 0.118 mol) was added and stirring was continued for 3 hours. The mixture was poured onto the ice water and the resulting off-white solid was collected by filtration to give 10.0 g (61%) of product m.p. 48-50 C. NMR (DMSO-d6, 300 MHz): delta1.3 (t, J=8.6 Hz, 3H), 4.28 (q, J=8.6 Hz, 2H), 7.25 (m, 2H), 7.60 (m, 2H).
In an ice-bath,To a solution of 2-chloro-1H-benzo[d]imidazole (1.31 mmol) in N,N-dimethylformamide (6 mL) was added NaH (60% dispersion in paraffin, 1.57 mmol). after 20 minutes,Iodoethane (1.57 mmol) was added,The mixture was left at room temperature. 2 hours later,The reaction is quenched with water,Extraction with EtOAc (2x).The resulting organic phase is washed with brine,Dried over Na2SO4 and concentrated to give A2 as a yellow oil.
To a solution of 2-Chloro-1- isopropyl-1H-benzoimidazole (167.5 mg, 1.00 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 36 mg, 1.2 mmol) at 0 oC. After stirring 30 minutes at r.t., 2-Bromo-propane (244 mg, 1.20 mmol) was added dropwise and the reaction mixture was stirred at 37 oC for 12 hours. Then the reaction was quenched by water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine and dried over Na2SO4. The mixture was filtered and the filtrate solvent was removed under reduced pressure. The residue was purified via silica gel column chromatography (Petroleum ether/EtOAc) to give the title compound (105 mg, 53.2% yield) as a white solid. LC-MS: Calculated exact mass = 194.1; Found [M+H]+ =195.2; 197.2.
47%
General procedure: 2-Chloro-1H-benzoimidazole (3.04 g, 20 mmol) was dissolved in dry DMF (15 mL) at 0 C, to the solution was added NaH (0.91 g, 22.7 mmol), and the mixture was stirred for 1 h at 0 C, then halide (21.6 mmol) was added. The mixture was stirred overnight at room temperature and was poured into water (50 mL) and stirred for 1 h, filtrated, washed with water and dried to afford 4a-d.
With potassium carbonate; In methanol; dichloromethane; dimethyl sulfoxide;
EXAMPLE 13 6,7-Dimethoxy-2-[4-[1-(1-methylethyl)-1H-benzimidazol-2-yl]-1-piperazinyl]-4-quinazolinamine (Ia: R3 =1-(1-methylethyl)-1H-benzimidazol-2-yl; R4, R5, R6 and R9 =H; R7 and R8 =OMe; and n=1) A mixture of 2-chlorobenzimidazole (2.0 g), isopropyl bromide (1.36 ml) and potassium carbonate (34 g) in dimethyl sulfoxide (200 ml) was heated at 60 C. for 6 hr and poured into ice. The resulting mixture was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed through silica gel using 5% methanol in dichloromethane. The appropriate fractions were evaporated to give 2-chloro-1-(1-methylethyl)benzimidazole, mp 58-60 C. Similarily, by replacing isopropyl bromide with propyl bromide, 2-chloro-1-propylbenzimidazole, nmr (CDCl3) delta 0.95 (t, 3H), 1.85 (m, 2H), 4.1 (t, 2H), 7.25 (m, 3H) and 7.65 (m, 1H), was obtained.
To a solution of 2-chloro-1H- benzo[d]imidazole (1 g, 6.553 mmol) in DMF (50 mL) was added NaH (340.8 mg, 8.519 mmol) at 0 oC. After 15 minutes, bromoethane (1.33 g, 8.519 mmol) was added to the reaction mixture at 0 oC. The reaction mixture was stirred at r.t. for 2 hours. TLC (Petroleum ether/EtOAc = 5/1; silica gel plate) showed complete consumption of the starting material after this time. The mixture was quenched by water at 0 oC. The reaction mixture was extracted with EtOAc (50 mL x 2), washed with brine and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified via column chromatography (Petroleum ether/EtOAc) to give the title compound (1.1 g, 92.7% yield) as a white solid. LC- MS: Calculated exact mass = 180.1; Found [M+H]+ = 181.1.
73%
General procedure: 2-Chloro-1H-benzoimidazole (3.04 g, 20 mmol) was dissolved in dry DMF (15 mL) at 0 C, to the solution was added NaH (0.91 g, 22.7 mmol), and the mixture was stirred for 1 h at 0 C, then halide (21.6 mmol) was added. The mixture was stirred overnight at room temperature and was poured into water (50 mL) and stirred for 1 h, filtrated, washed with water and dried to afford 4a-d.
General procedure: A mixture of 2-chloro-5-methyl-benzimidazole (10.2 g, 61.2 mmol) and hydrazine monohydrate (59 mL, 1.22 mol) was stirred at 100 C overnight. After being cooled to ambient temperature, to the reaction mixture was added to water (60 mL). After stirring under ice cooling, the resulting precipitates were collected by filtration. The precipitates were washed with water 3 times, and then dried in vacuo to give 2-hydrazino-5-methyl-benzimidazole (8.4 g, 84.6%).
900 mg
With hydrazine hydrate; at 140℃;
A mixture of chlorobenzimidazole (1 g, 6.554 mmol) in hydrazine hydrate (10.2 mL) was stirred overnight at 140 C. The precipitate was filtered and washed with cold water to give 2-hydrazinyl-lH-benzo[d]imidazole (900 mg, 6.07 mmol) as a grey solid. MS (ES+) m/z 149.0 (M+l).
General procedure: In a 50 mL round bottom flask, 0.86 gm (0.01 mol) of piperazine and 1.58 gm(0.01 mol) of <strong>[142-64-3]piperazine dihydrochloride</strong> were added in 20 mL of water and stirred forhalf hour. 0.68 gm (0.01 mol) of Imidazole, 0.274 gm (0.001 mol) of tributylbenzylammonium choride, 1.69 gm (0.01 mol) 2-chlorobenzothiazole and 2gm NaCl(aq) wereadded in the reaction mixture and refluxed for 10 hrs. The progress of reaction wasmonitored by TLC. After completion of the reaction, aqueous layer was washed withethyl acetate (3 x 10 ml). The combined organic layer was dried over anhydrous Na2SO4and concentrated at reduced pressure. Products were purified either by crystallizing or byflash chromatography.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: To a stirred solution of 1c (1.0 eq.) and POCl3 (10 eq.) was addeda few drops of conc. HCl. The reaction mixture was heated to 150 C and stirred for 3 h. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with 1 N aq. NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to givecrude product 1d. Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: To a stirred solution of 1c (1.0 eq.) and POCl3 (10 eq.) was addeda few drops of conc. HCl. The reaction mixture was heated to 150 C and stirred for 3 h. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with 1 N aq. NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to givecrude product 1d. Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: To a stirred solution of 1c (1.0 eq.) and POCl3 (10 eq.) was addeda few drops of conc. HCl. The reaction mixture was heated to 150 C and stirred for 3 h. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with 1 N aq. NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to givecrude product 1d. Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: To a stirred solution of 1c (1.0 eq.) and POCl3 (10 eq.) was addeda few drops of conc. HCl. The reaction mixture was heated to 150 C and stirred for 3 h. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with 1 N aq. NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to givecrude product 1d. Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 12h;
General procedure: To a stirred solution of 1c (1.0 eq.) and POCl3 (10 eq.) was addeda few drops of conc. HCl. The reaction mixture was heated to 150 C and stirred for 3 h. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with 1 N aq. NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to givecrude product 1d. Alternatively, to a stirred mixture of 2-chlorobenzimidazole (1.0 eq.) and R3CH2Br (1.0 eq.) in dimethylformamide was added N,N-diisopropylethylamine (1.5 eq.). The reaction mixture was heated to 110 C and stirred for 12 h. After the reaction was completed, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate/hexane) to give desired product 1d.
1-(5-chloro-pentyl)-2-chloro-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.5%
With tetrabutylammomium bromide; sodium hydroxide; In water; at 60℃; for 2.08333h;
The 2-Chloro-1H-benzimidazol(15.2 g, 0.10 mol) was dissolved in 200mL of 20 wt% sodium hydroxide aqueous solution and then was added with Bromo-5-chloro-pentane (36.8 g, 0.20 mol), tetrabutylammonium bromide (1.0 g, 0.003 mol); it is then mixed and stirred for 5 minutes, heated to 60C and react for 2 hours under stirring. The reaction solution was cooled to room temperature, and extracted with 100 mL of dichloromethane and the liquid was separated; and 100 mL of dichloromethane was then added to aqueous phase, and then the organic phases were combined and washed with 100 mL of saturated saline solution and the liquid was separated; and the organic phase was evaporated to obtain oily substance. The oily substance was then purified by chromatography separation using neutral Al2O3 to obtain 16.0 g of 1-(5-chloro-pentyl)-2-chloro-1H-benzimidazol, with a yield of 62.5%.
Compound 2 (364 mg, 1 mmol, 1 Oeq), <strong>[148893-10-1]HATU</strong> (760.4 mg, 2 Oeq), DIPEA (0.552 ml, 3 Oeq) was added to 10 mL DCM, 30 C stirring After 0.5 hours, 2-chlorobenzimidazole (152.5 mg, 1 Oeq) was added and stirring was continued for 24 hours. The solid formed in the reaction was filtered under reduced pressure and the filter cake was washed successively with 5 mL of DCM, 2 mL of methanol and 5 mL of H20 to give a yellow solid (48%).
N-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)-N-methylpropionamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With dipotassium peroxodisulfate; potassium iodide; at 80℃; for 6h;Schlenk technique;
General procedure: A 50 mL Schlenk tube equipped with a stirrer bar was charged with KI (16.6 mg, 0.1 mmol), benzotriazole (59.5 mg, 0.5 mmol), DMA (2 mL), and K2S2O8 (270 mg, 1 mmol) under air. The mixture was then stirred at 80 C for 6 h (TLC monitoring), poured into H2O (20 mL), and extracted with EtOAc (3 ×). Then the organic phase was evaporated under vacuum, and the crude product was purified by column chromatography [silica gel, PE-EtOAc (10:1 to 2:1)] to give a colorless oil; yield: 98 mg (96%);
2-chloro-1-(3-chloro-4-fluorobenzyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
120 mg
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step C: The crude 2-chlorobenzimidazole (100 mg, 0.575 mmol, 1 eq) was dissolved in DMF (5 mL) in a reaction vial. Potassium carbonate (95 mg, 0.69 mmol, 1.2 eq) was added to the reaction, followed by <strong>[192702-01-5]4-fluoro-3-chlorobenzylbromide</strong> (0.093 mL, 0.69 mmol, 1.3 eq). The reaction was stirred at room temperature and monitored by LCMS. Upon conversion of the starting material, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water (2*) and a brine solution, dried over magnesium sulfate, and concentrated to afford a crude solid. The crude solid was purified by column chromatography to afford the 2-chloro-1-(3-chloro-4-fluorobenzyl)-1H-benzo[d]imidazole as a white solid (120 mg, 71%).
2-(2,6-dibromophenoxy)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N-ethyl-N,N-diisopropylamine;Inert atmosphere; Reflux;
Synthesis of 2-(2,6-dibromophenoxy)-1H-benzo[d]imidazole In a 250 mL round bottom flask equipped with a reflux condenser, a mixture of 2-chlorobenzimidazole (8.97 g, 58.8 mmol) and <strong>[608-33-3]2,6-dibromophenol</strong> (17.8 g, 70.7 mmol) in N,N-diisopropylethylamine (41 mL) was stirred at reflux under argon for 17 h. The reaction mixture was then allowed to cool to room temperature, and CH2Cl2 (100 mL) was added. This suspension was stirred at room temperature for 2 h. It was then filtered and rinsed with CH2Cl2 (25 mL) and dried overnight in vacuo to give 2-(2,6-dibromophenoxy)-1H-benzo[d]imidazole as a very light beige solid (14.7 g, 68% yield).
General procedure: In a round bottom flask fitted with amagnetic stirrer, 2-chloro-1H-benzimidazole, 3, (0.50 g, 3.3 mmol) was dissolved in DMSO (3mL) and then NaH (60%; 0.19 g, 4.9 mmol) was added at 0 C and stirred for 1h. Next, benzylbromide (0.67 g, 3.9 mmol) was added to the suspension and the reaction was stirred at rt for 12h. Ice-cold water (15 mL) was added to the mixture and resulting precipitate was collected viafiltration. The filtrate was washed with water and dried under vacuum to give desired product, 4,as a white solid (0.75 g, 88%). LCMS: RT = 2.69 min., >98% 215 and 254 nm, m/z = 243.0 [M+ H]+. 1H NMR (499 MHz, CDCl3) delta 7.68 (d, J = 7.4 Hz, 1H), 7.35 - 7.24 (m, 5H), 7.16 (d, J =6.8 Hz, 2H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) delta 141.33, 134.83, 128.99, 128.22, 126.76,123.53, 123.05, 119.18, 109.98, 47.94.
General procedure: In a round bottom flask fitted with amagnetic stirrer, 2-chloro-1H-benzimidazole, 3, (0.50 g, 3.3 mmol) was dissolved in DMSO (3mL) and then NaH (60%; 0.19 g, 4.9 mmol) was added at 0 C and stirred for 1h. Next, benzylbromide (0.67 g, 3.9 mmol) was added to the suspension and the reaction was stirred at rt for 12h. Ice-cold water (15 mL) was added to the mixture and resulting precipitate was collected viafiltration. The filtrate was washed with water and dried under vacuum to give desired product, 4,as a white solid (0.75 g, 88%). LCMS: RT = 2.69 min., >98% 215 and 254 nm, m/z = 243.0 [M+ H]+. 1H NMR (499 MHz, CDCl3) delta 7.68 (d, J = 7.4 Hz, 1H), 7.35 - 7.24 (m, 5H), 7.16 (d, J =6.8 Hz, 2H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) delta 141.33, 134.83, 128.99, 128.22, 126.76,123.53, 123.05, 119.18, 109.98, 47.94.
2-chloro-1-(3-fluoro-4-methoxybenzyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: In a round bottom flask fitted with amagnetic stirrer, 2-chloro-1H-benzimidazole, 3, (0.50 g, 3.3 mmol) was dissolved in DMSO (3mL) and then NaH (60%; 0.19 g, 4.9 mmol) was added at 0 C and stirred for 1h. Next, benzylbromide (0.67 g, 3.9 mmol) was added to the suspension and the reaction was stirred at rt for 12h. Ice-cold water (15 mL) was added to the mixture and resulting precipitate was collected viafiltration. The filtrate was washed with water and dried under vacuum to give desired product, 4,as a white solid (0.75 g, 88%). LCMS: RT = 2.69 min., >98% 215 and 254 nm, m/z = 243.0 [M+ H]+. 1H NMR (499 MHz, CDCl3) delta 7.68 (d, J = 7.4 Hz, 1H), 7.35 - 7.24 (m, 5H), 7.16 (d, J =6.8 Hz, 2H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) delta 141.33, 134.83, 128.99, 128.22, 126.76,123.53, 123.05, 119.18, 109.98, 47.94.
2-chloro-1-(2-chloro-4-fluorobenzyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: In a round bottom flask fitted with amagnetic stirrer, 2-chloro-1H-benzimidazole, 3, (0.50 g, 3.3 mmol) was dissolved in DMSO (3mL) and then NaH (60%; 0.19 g, 4.9 mmol) was added at 0 C and stirred for 1h. Next, benzylbromide (0.67 g, 3.9 mmol) was added to the suspension and the reaction was stirred at rt for 12h. Ice-cold water (15 mL) was added to the mixture and resulting precipitate was collected viafiltration. The filtrate was washed with water and dried under vacuum to give desired product, 4,as a white solid (0.75 g, 88%). LCMS: RT = 2.69 min., >98% 215 and 254 nm, m/z = 243.0 [M+ H]+. 1H NMR (499 MHz, CDCl3) delta 7.68 (d, J = 7.4 Hz, 1H), 7.35 - 7.24 (m, 5H), 7.16 (d, J =6.8 Hz, 2H), 5.38 (s, 2H). 13C NMR (126 MHz, CDCl3) delta 141.33, 134.83, 128.99, 128.22, 126.76,123.53, 123.05, 119.18, 109.98, 47.94.
PREPARATION 1.2 Synthesis of 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) and dimethylformamide (200 mL). Add portionwise, sodium hydride (24.0 g, 60% in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl ethyl ether (21.9 g, 201,5 mmol). Heat to 60 C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate. Extract with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluding sequentially with 10% ethyl acetate/hexane and then 30% ethyl acetate hexane to give the 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: Rf =0.74 (silica gel, 7/3 ethyl acetate/hexane).
6-((2-chloro-1H-benzo[d]imidazol-1-yl)methyl)nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In acetonitrile; at 20℃; for 12h;
General procedure: 2-chloro-4,6-difluoro-1H-benzo[d]imidazole (50.0 g, 265.0 mmol, 1.0 equiv) and 6-(chloromethyl)nicotinoniiTile (40.5 g, 265.0 mmol, 1.0 equiv) was dissolved in acetonitrile (500.0 mL, 10.0 mL/g) at room temperature. Cesium carbonate (138.0 g, 427.0 mmol, 1.6 equiv) was added and the mixture was stirred at room temperature for 12b. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrate under reduced pressure. The crude material was adsorbed onto a plug of silica gel (60-120 mesh) and purified by column chromatography, eluting with a gradient of 25% ethyl acetate in hexane to provide 6-((2
2-chloro-1-(4-methylpyridin-2-yl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
5%
With copper(l) iodide; potassium carbonate In dimethyl sulfoxide at 130℃; for 24h; Schlenk technique;
4.3. General procedure for synthesis of ligand (L3)
2Fluoro4methylpyridine (1.0 mmol, 105 lL), 2chloro1Hbenzo[d]imidazole (1.1 mmol, 171.3 mg), K2CO3 (3.0 mmol,414.0 mg) and DMSO (2 mL) were successively put into a 25 mLSchlenk tube. The Schlenk tube was put into the magnetic stirrerand heated under 130 C for 24 h. After the reaction, brine(30 mL) was added to dilute the reaction mixtures and extractedthree times with dichloromethane (3 30 mL). Then the organicphase was dried and collected, the solvent was removed under vacuum,and the desired product L3 was purified by column chromatographyand characterized by NMR, HRMS and IRspectroscopy. Purification for 2chloro1(4methylpyridin2yl)1H-benzo[d]imidazole by flash chromatography (petroleumether/EtOAc = 15:1) gave a colorless oil (12.2 mg, 5%). 1H NMR(400 MHz, CDCl3) d 8.56 (d, J = 4.2 Hz, 1H), 7.75-7.73 (m, 1H),7.41-7.39 (m, 1H),7.34-7.26 (m, 4H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3): d 150.7, 149.5, 148.5, 141.7, 139.2, 135.6,125.0, 124.1, 123.5, 121.9, 119.5, 111.2, 21.2. IR (KBr, neat):3061, 1604, 1456, 1355, 1302, 1260, 1158, 748 cm1. HRMS (ESI)m/z: [M + H]+ Calcd for C13H11ClN3 244.0642; Found 244.0639.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
