SQ-109, -Drug Synthesis Database

【结构式】

【药物名称】SQ-109

【化学名称】N¹-(2-Adamantyl)-N2-(3,7-dimethyl-2,6-octadienyl)-ethane-1,2-diamine

【CA登记号】502487-67-4;627519-90-8 (monohydrochloride);627526-74-3 (trifluoroacetate);627526-76-5 (dihydrochloride);652978-09-1 (acetate)

【分子式】C₂₂H₃₈N₂

【分子量】330.5562

【开发单位】Sequella, Inc. (US).

【药理作用】Treatment of tuberculosis, Cell wall biosynthesis inhibitor

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

合成路线2

In an adapted method, complete solution-phase synthesis of SQ-109 is achieved by the substitution of (2E)-1-bromo-3,7-dimethylocta-2,6-diene (VIII) by ethylene diamine (IX) at –78 °C in dry DCM to give (E)-N’-(3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (X) (4, 5). Finally, amine (X) is made to undergo reductive amination with 2-adamantanone (XI) in MeOH using NaBH4 under an N2 atmosphere overnight to give SQ-109, which can be extracted with ethyl acetate or converted to a hydrochloride salt using HCl and MeOH. Scheme 2.

参考文献中间体

【4】 Onajole, O.K., Govender, P., van Helden, P.D., Kruger, H.G., Maguire, G.E., Wiid, I., Govender, T. Synthesis and evaluation of SQ109 analogues as potential anti-tuberculosis candidates. Eur J Med Chem 2010, 45(5): 2075-9.
【5】 Onajole, O.K., Sosibo, S., Govender, P. et al. Novel linear diamine disubstituted polycyclic ‘cage’ derivatives as potential antimycobacterial candidates. Chem Biol Drug Design 2011, 78(6): 1022-30.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	31116	(2E)-1-bromo-3,7-dimethyl-2,6-octadiene; trans-Geranyl bromide; Geranyl bromide	6138-90-5	C₁₀H₁₇Br	详情	详情
(IX)	14754	ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine	107-15-3	C₂H₈N₂	详情	详情
(X)	66063	(E)-N’-(3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine		C₁₂H₂₄N₂	详情	详情
(XI)	40404	2-adamantanone	700-58-3	C₁₀H₁₄O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)