Novel benzoimidazole derivatives useful as antiproliferative agents
A technology of benzimidazole and solvates, which can be applied in drug combinations, antineoplastic drugs, anti-infective drugs, etc., and can solve problems such as proliferation disorders and malignancy
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[0215] Preparation of general intermediates:
[0216] 8-Benzyloxy-2-chloro-quinoline
[0217] in dry N 2 2,8-Quinolinediol (133.3 g, 0.827 mol) was dissolved in 800 mL of anhydrous DMF under atmosphere. Potassium carbonate (183 g, 1.32 mol) was added to this solution, followed by benzyl bromide (110 mL, 0.909 mol), and the solution was heated to 65° C. and reacted at this temperature overnight. The reaction mixture was then poured into 9 L of water, and the resulting solution was stirred at room temperature for 5.5 hours, then it was filtered. The solid was washed with water, collected and suspended in toluene, and finally the solution was concentrated under vacuum to give 142 g of 8-benzyloxy-quinolin-2-ol. This material (142g, 0.565mol) was dissolved in dry N 2 Dissolve in 500mL DCE under atmosphere. To this solution was added dropwise oxalyl chloride (99 mL, 1.13 mol), followed by 1 mL DMF. After the addition was complete, the reaction ...
Embodiment 1
[0221] Preparation of {1-[2-(5-Hydroxy-benzimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (compound H)
[0222] 5-Hydroxy-benzimidazole intermediate H can be prepared by the method outlined in Scheme 2.
[0223] Scenario 2
[0224]
[0225] Preparation of Compound B
[0226] 8-(tert-Butyl-dimethyl-silanyloxy)-quinolin-2-yl trifluoro-methanesulfonate.
[0227] In dry nitrogen (N 2 2,8-quinolinediol (A) (20.0 g, 124 mmol) was suspended in 500 mL of dichloromethane (DCM) under an atmosphere of . To this solution was added imidazole (20.3 g, 298 mmol), followed by t-butyldimethylsilyl chloride (20.6 g, 137 mmol) and 4-dimethylaminopyridine (1.50 g, 12.4 mmol). The reaction mixture was stirred overnight at room temperature, then dissolved in DCM and 1% sodium bisulfate (NaHSO 4 ) between aqueous solutions. Keep the DCM layer and refill with 1% NaHSO 4 Washed twice with aqueous solution, then washe...
Embodiment 2
[0251] Preparation of 1-[2-(5-cyclopropylmethoxy-benzimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine
[0252] in dry N 2 (1-[2-(5-Hydroxy-benzimidazol-1-yl)-quinolin-8-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester H (200mg, 0.435mmol ) was dissolved in 1.5mL dry DMF. Add Cs to this solution 2 CO 3 (170 mg, 0.520 mmol), followed by cyclopropylmethane bromide (46 mL, 0.48 mmol). The reaction mixture was then heated to 65°C and stirred at this temperature for 4 hours. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was washed 4 more times with water, then brine. followed by Na 2 SO 4 The EtOAc was dried, filtered and concentrated in vacuo and the resulting green oil was flash chromatographed on silica gel eluting with MeOH / dichloromethane (DCM) (2:98) to give a green oil. in dry N 2 This oil was dissolved in 1.5 mL of TFA under atmosphere. The reaction mixture was stirred at room temperature for 10...
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