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【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】 

与该中间体有关的原料药合成路线共 1 条

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
Extended Information