* 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.
Step A: 2-Chloro-4-methyl-l -benzo[d]imidazole To 4-methyl-lH-benzo[d]imidazol-2(3H)-one (1.5 g, 10 mmol) was added POCb (19 ml, 200 mmol) and the reaction mixture was heated to 135 °C for 3 hours. The reaction was then cooled to room temperature and the excess POCb was removed in vacuo. The solid residue was diluted carefully with water and then slowly neutralized with saturated NaHCC until the pH was ~7-8. The mixture was extracted with ethyl acetate (2 x 150 mL) and the organics extracts were combined. The organics were dried with MgS04, filtered, and the solvent was removed to yield the crude residue. The crude material was purified by chromatography (Biotage) to yield 2-chloro-7-methyl-lH- benzo[d]imidazole (1.1 g, 6.3 mmol, 62 percent yield) as a slightly yellow powder. MS (LC/MS) R.T. = 2.61 ; [M+]+ = 166.93
Reference：
[1] Patent: WO2016/73407, 2016, A1, . Location in patent: Page/Page column 56
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 15, p. 7188 - 7211
[3] Patent: US5273975, 1993, A,
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 18, p. 5010 - 5014
[5] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 4, p. 1071 - 1074
2
[ 19190-68-2 ]
[ 15965-57-8 ]
Yield
Reaction Conditions
Operation in experiment
93%
for 20 h; Heating / reflux
2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 ml of phosphoryl chloride are introduced into a 250 ml two-necked flask under an argon atmosphere, equipped with a magnetic stirrer. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 ml), the mixture is neutralized to pH=8 with 28percent aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 ml). After the usual work-up, the 2-chloro-4-methylbenzimidazole is obtained in a yield of 93percent (6.23 g). 1H NMR (300 MHz, δ ppm) DMSO-d6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
93% (6.23 g)
With ammonium hydroxide; trichlorophosphate In water
1.4.2. 2-Chloro-4-methylbenzimidazole 2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 mL of phosphoryl chloride are introduced into a 250 mL two-necked flask under an argon atmosphere, with magnetic stirring. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 mL), neutralized to pH=8 with 28percent aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 mL). After the usual work-up, the title product is obtained in a yield of 93percent (6.23 g). 1H NMR (300 MHz, δ ppm) DMSO D6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
General procedure: A mixture of 5-methyl-1,3-dihydrobenzimidazol-2-one (2) (24.4 g) and phosphoryl chloride (245 mL) was stirred at 90 C. for 5 hr. After cooling to room temperature, chloroform (250 mL) was added to the reaction mixture. After stirring at room temperature, the resulting precipitate was collected by filtration, and washed 5 times with chloroform (100 mL). To the precipitate was added a mixture of ethyl acetate and saturated sodium hydrogen carbonate solution. After stirring at room temperature, the organic phase was successively washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was powdered with hexane and diisopropyl ether to give 2-chloro-5-methyl-1H-benzimidazole (3) (20.4 g). [0104] ESI-HRMS (positive ion, sodium formate): calcd for C8H8ClN2([M+H]+) 167.0371. found 167.0391 [0105] NMR (DMSO-d6, delta): 2.40 (3H, s), 7.00-7.06 (1H, m), 7.29 (1H, s), 7.39 (1H, d, J=8.2 Hz)
11
[ 6974-32-9 ]
[ 15965-57-8 ]
2-chloro-4-methyl-1-[β-D-erythro-pentofuranosyl]-1H-benzimidazole[ No CAS ]
With trichlorophosphate; for 20h;Heating / reflux;
2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 ml of phosphoryl chloride are introduced into a 250 ml two-necked flask under an argon atmosphere, equipped with a magnetic stirrer. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 ml), the mixture is neutralized to pH=8 with 28% aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 ml). After the usual work-up, the 2-chloro-4-methylbenzimidazole is obtained in a yield of 93% (6.23 g). 1H NMR (300 MHz, delta ppm) DMSO-d6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
93% (6.23 g)
With ammonium hydroxide; trichlorophosphate; In water;
1.4.2. 2-Chloro-4-methylbenzimidazole 2-Hydroxy-4-methylbenzimidazole (5.92 g, 40 mmol) and 40 mL of phosphoryl chloride are introduced into a 250 mL two-necked flask under an argon atmosphere, with magnetic stirring. The mixture is refluxed for 20 hours and the phosphoryl chloride is evaporated off under vacuum. The solid obtained is taken up in water (250 mL), neutralized to pH=8 with 28% aqueous ammonia and the aqueous phase is extracted with ethyl acetate (3*250 mL). After the usual work-up, the title product is obtained in a yield of 93% (6.23 g). 1H NMR (300 MHz, delta ppm) DMSO D6: 2.47 (s, 3H), 7.01 (d, 1H), 7.11 (t, 1H), 7.32 (d, 1H).
Step A: 2-Chloro-4-methyl-l -benzo[d]imidazole To 4-methyl-lH-benzo[d]imidazol-2(3H)-one (1.5 g, 10 mmol) was added POCb (19 ml, 200 mmol) and the reaction mixture was heated to 135 C for 3 hours. The reaction was then cooled to room temperature and the excess POCb was removed in vacuo. The solid residue was diluted carefully with water and then slowly neutralized with saturated NaHCC until the pH was ~7-8. The mixture was extracted with ethyl acetate (2 x 150 mL) and the organics extracts were combined. The organics were dried with MgS04, filtered, and the solvent was removed to yield the crude residue. The crude material was purified by chromatography (Biotage) to yield 2-chloro-7-methyl-lH- benzo[d]imidazole (1.1 g, 6.3 mmol, 62 % yield) as a slightly yellow powder. MS (LC/MS) R.T. = 2.61 ; [M+]+ = 166.93
With hydrogenchloride; ammonium hydroxide; In chloroform; water; trichlorophosphate;
Part B. 2-Chloro-4-methyl-1H-benzimidazole Hydrogen chloride gas was bubbled through a stirred mixture of 4-methyl-1H-benzimidazolidone (5 g, 0.034 mol) in phosphorus oxychloride (50 mL) for 1 hour at 120 C. The solvent was removed and the resulting solid was dissolved in water (50 mL). Ammonium hydroxide (20 mL) was carefully added until the mixture was basic. The aqueous phase was then extracted with chloroform, filtered through celite, and evaporated to give 5.2 g, of brown oil. The product was chromatographed on silica gel in chloroform, and was eluted with 1% methanol:chloroform to give 3.96 g of brown oil. Crystallization from ethyl acetate:hexane gave 2.72 g of brown crystals, mp 137.5-139.5 C.
With trichlorophosphate; at 95℃; for 1.5h;
General procedure: A mixture of 5-methyl-1,3-dihydrobenzimidazol-2-one (1.00 g, 6.84 mmol) and phosphorous oxychloride (9.54 mL, 103 mmol) was stirred for 1.5 h at 95 C. After being cooled to ambient temperature, the reaction mixture was carefully added to a mixture of saturated NaHCO3 aq. (60 mL) and ethyl acetate (60 mL). The separated organic layer was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was evaporated in vacuo, The resulting precipitates were collected by filtration, and successfully washed with isopropyl ether to give 2-chloro-5-methyl-benzimidazole (1.74 g, 58.9 %).
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%).
(8-methyl-3H-1'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,3'-bicyclo[2.2.2]octan]-1'-yl-8-ium)trihydroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
Step B: (8-Methyl-3H-l '-azaspiro[benzo[4,5]imidazo[2, l-b]oxazole-2,3 '- bicyclo[2.2.2]octan]-l '-yl-8-ium)trihydroborate To 2-chloro-7-methyl-lH-benzo[d]imidazole (0.65 g, 3.9 mmol) from example 10, step A, in THF (35 mL) was added n-butyllithium (1.6 mL, 3.9 mmol) dropwise at - 78C. After 45 minutes, a solution of racemic (l'-azaspiro[oxirane-2,3'- bicyclo[2.2.2]octan]-l'-yl-4-ium)trihydroborate (0.66 g, 4.29 mmol) from the reference example, in THF (10 mL) was added dropwise at -78C. The cooling bath ws removed and the reaction mixture warmed to room temperature. After 15 minutes, the mixture was heated to 75C for 2 hours and then cooled to room temperature. The reaction was quenched with water and the product was extracted with ethyl acetate (100 mL). The organics were dried with MgS04, filtered and the solvent was removed to yield the crude product. The crude material was purified by chromatography (Biotage) to yield racemic (8-methyl-3H-l'-azaspiro[benzo[4,5]imidazo[2, l-b]oxazole-2,3'-bicyclo[2.2.2]octan]-r- yl-10-ium)trihydroborate (0.40 g, 1.4 mmol, 52%). The 5-methyl regioisomer product was not observed. MS (LC/MS) R.T. = 1.90; [M+1-BH3]+ = 270.07.
52%
To 2-chloro-7-methyl-1H-benzo[d]imidazole (0.65 g, 3.9 mmol) from example 10, step A, in THF (35 mL) was added n-butyllithium (1.6 mL, 3.9 mmol) dropwise at -78C. After 45 minutes, a solution of racemic (1'-azaspiro[oxirane-2,3'-bicyclo[2.2.2]octan]-1'-yl-4-ium)trihydroborate (0.66 g, 4.29 mmol) from the reference example, in THF (10 mL) was added dropwise at -78C. The cooling bath ws removed and the reaction mixture warmed to room temperature. After 15 minutes, the mixture was heated to 75C for 2 hours and then cooled to room temperature. The reaction was quenched with water and the product was extracted with ethyl acetate (100 mL). The organics were dried with MgSO4, filtered and the solvent was removed to yield the crude product. The crude material was purified by chromatography (Biotage) to yield racemic (8-methyl-3H-1'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,3'-bicyclo[2.2.2]octan]-1'-yl-10-ium)trihydroborate (0.40 g, 1.4 mmol, 52%). The 5-methyl regioisomer product was not observed. MS (LC/MS) R.T. = 1.90; [M+1-BH3]+ = 270.07.
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