【结 构 式】 |
【分子编号】66061 【品名】Resin-attached N-geranyl-N’-(2-adamantyl)glycinamide 【CA登记号】 |
【 分 子 式 】 【 分 子 量 】 【元素组成】 |
合成路线1
该中间体在本合成路线中的序号:(VI)Two main strategies have been used to synthesize SQ-109, including a solid-phase approach (1), which was later adapted for solutionphase synthesis (2). In the solid-phase strategy, Rink acid resin is activated at room temperature using triphenylphosphine and hexachloroethane in THF. The activated resin is then loaded with a solution of EtN(i-Pr)2 and (2E)-3,7-dimethylocta-2,6-dien-1-amine (geranylamine, I) in dichloroethane for 8 hours at 45 °C, followed by 6-8 hours at room temperature. The resulting geranylamine-attached resin (II) is then loaded with pyridine and chloroacetyl chloride (III) in THF for 8 hours at 45 °C, followed by 6-8 hours at room temperature to give resin-attached N-geranyl-a-chloroacetamide (IV), which is loaded with EtN(i-Pr)2 and a suspension of 2-adamantamine hydrochloride (V) in DMF at 70-75°C for 16 hours to give resin-attached N-geranyl-N’-(2-adamantyl)glycinamide (VI). Glycinamide (VI) is then reduced in anhydrous THF by adding Red-Al in toluene and stirring for 4 hours at room temperature to yield resin-attached N-geranyl-N’-(2-adamantyl)ethane-1,2-diamine (VII). In the last step, the resin is loaded with TFA and dichloromethane followed by the addition of MeOH to cleave the resin-linked product before filtration. The filtrate is collected and dried to give the trifluoroacetate salt of N-geranyl-N’-(2-adamanthyl)ethane-1,2-diamine (SQ-109), which is further purified by HPLC to give the diacetate salt (3). Scheme 1.
【1】 Lee, R.E., Protopopova, M., Crooks, E., Slayden, R.A., Terrot, M., Barry, C.E. 3rd. Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. J Comb Chem 2003, 5(2): 172-87. |
【2】 Tahlan, K., Wilson, R., Kastrinsky, D.B. et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother 2012, 56(4): 1797-809. |
【3】 Protopopova, M.N., Lee, R.E., Slayden, R.A., Barry, C.E.I., Bogatcheva, E., Einck, L. (US Department of Health & Human Services; Sequella, Inc.). Anti tubercular drug: Compositions and methods. JP 2005526129, US 2003236225, US 2004019117, US 2004033986, US 6951961, US 8268894, WO 2003096989. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 66057 | Geranylamine; Trans-3,7-Dimethyl-2,6-Octadien-1-ylamine, Trans-3,7-Dimethyl-2,6-Octadienyl Amine | 6246-48-6 | C10H19N | 详情 | 详情 |
(II) | 66058 | Geranylamine-attached resin | 详情 | 详情 | ||
(III) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
(IV) | 66059 | Resin-attached N-geranyl-α-chloroacetamide | 详情 | 详情 | ||
(V) | 66060 | 2-Adamantanamine hydrochloride; 2-Aminoadamantane hydrochloride; Tricyclo[3.3.1.1(3.7)]dec-2-ylamine hydrochloride | 10523-68-9 | C10H17N.HCl | 详情 | 详情 |
(VI) | 66061 | Resin-attached N-geranyl-N’-(2-adamantyl)glycinamide | 详情 | 详情 | ||
(VII) | 66062 | Resin-attached N-geranyl-N’-(2-adamantyl)ethane-1,2-diamine | 详情 | 详情 |