Baogongteng A, -Drug Synthesis Database

【结构式】

【药物名称】Baogongteng A

【化学名称】(-)-6beta-Acetoxy-2beta-hydroxynortropane benzoate
　　　　　　(1R,2S,5R,6S)-6-(Acetyloxy)-2-hydroxy-8-azoniabicyclo[3.2.1]octane benzoate

【CA登记号】74239-84-2 (free base)

【分子式】C₁₆H₂₁NO₅

【分子量】307.34947

【开发单位】Shanghai Medical University (Originator)

【药理作用】Antiglaucoma Agents, Miotics, OCULAR MEDICATIONS, Ophthalmic Drugs

合成路线1 合成路线2

合成路线1

The synthesis of baogongteng A has been published: The alkylation of 3-hydroxypyridine (I) with benzylbromide (II) gives 1-benzyl-3-hydropyridinium bromide (III), which is condensed with acrylonitrile (IV) by means of triethylamine at reflux temperature, yielding the bicyclic nitrile (V). The reduction of (V) with LiAlH4 gives the bicyclic hydroxy nitrile (VII), also obtained by stepwise reduction of (V) with H2 over Pd/C to (VI) and posterior reduction to (VII) with NaBH4. The protection of (VII) with trimethylsilyl chloride and triethylamine affords the silyloxy derivative (VIII), which is treated with methylmagnesium iodide to yield the acetyl derivative (IX). Oxidation of (IX) with m-chloroperbenzoic acid (MCPBA) in CHCl3 affords the acetoxy compound (X), which is finally debenzylated by hydrogenation with H2 and Pd/C in ethanol to give the free base (XI). This is then treated with benzoic acid.

参考文献中间体

【1】 Zeng, L.M.; Jung, M.E.; Peng, T.S.; Zeng, H.Y.; Le, Y.; Su, J.Y.; Total synthesis of Bao Gong Teng-A, a natural antiglaucoma compound. J Org Chem 1992, 57, 13, 3528.

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)	12911	3-Hydroxypyridine; 3-Pyridinol	109-00-2	C₅H₅NO	详情	详情
(II)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(III)	12913	1-Benzyl-3-hydroxypyridinium bromide		C₁₂H₁₂BrNO	详情	详情
(IV)	10847	Acrylonitrile	107-13-1	C₃H₃N	详情	详情
(V)	12915	8-Benzyl-2-oxo-8-azabicyclo[3.2.1]oct-3-ene-6-carbonitrile		C₁₅H₁₄N₂O	详情	详情
(VI)	12916	8-Benzyl-2-oxo-8-azabicyclo[3.2.1]octane-6-carbonitrile		C₁₅H₁₆N₂O	详情	详情
(VII)	12917	8-Benzyl-2-hydroxy-8-azabicyclo[3.2.1]octane-6-carbonitrile		C₁₅H₁₈N₂O	详情	详情
(VIII)	12918	8-Benzyl-2-[(trimethylsilyl)oxy]-8-azabicyclo[3.2.1]octane-6-carbonitrile		C₁₈H₂₆N₂OSi	详情	详情
(IX)	12919	1-(8-Benzyl-2-hydroxy-8-azabicyclo[3.2.1]oct-6-yl)-1-ethanone		C₁₆H₂₁NO₂	详情	详情
(X)	12920	8-benzyl-2-hydroxy-8-azabicyclo[3.2.1]oct-6-yl acetate		C₁₆H₂₁NO₃	详情	详情
(XI)	12921	2-hydroxy-8-azabicyclo[3.2.1]oct-6-yl acetate		C₉H₁₅NO₃	详情	详情
(XII)	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情

合成路线2

The bromination of the acetoxytropanone (I) with Br2 gives the bromo derivative (II), which is treated with Ag2CO3 to yield the hydroxy compound (III). The reaction of (III) with ethane-1,2-dithiol (IV) in acid medium affords the cyclic dithioketal (V), which is desulfurized with H2 over Raney-Ni providing the tropanol derivative (VI). The oxidation of (VI) with CrO3 gives the tropanone derivative (VII), which is stereoselectively reduced with NaBH4, yielding the tropanol compound (VIII). Finally, this compound is demethylated by reaction with 2,2,2-trichloroethyl chloroformate and reduction with Zn and acetic acid.

参考文献中间体

【1】 Liu, J.; Synthesis of biologically active alkaloids of Chinese medicinal herbs. Drugs Fut 1994, 19, 3, 265-278.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Va)	41174			C₁₂H₁₉NO₃S₂	详情	详情
(Vb)	41175			C₁₂H₁₉NO₃S₂	详情	详情
(I)	41171	(1R,5R,6S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]oct-6-yl acetate		C₁₀H₁₅NO₃	详情	详情
(II)	41172	(1R,2S,5R,6S)-2-bromo-8-methyl-3-oxo-8-azabicyclo[3.2.1]oct-6-yl acetate		C₁₀H₁₄BrNO₃	详情	详情
(III)	41173	(1R,2R,5R,6S)-2-hydroxy-8-methyl-3-oxo-8-azabicyclo[3.2.1]oct-6-yl acetate		C₁₀H₁₅NO₄	详情	详情
(IV)	27313	1,2-ethanedithiol	540-63-6	C₂H₆S₂	详情	详情
(VI)	41176	(1R,2R,5R,6S)-2-hydroxy-8-methyl-8-azabicyclo[3.2.1]oct-6-yl acetate		C₁₀H₁₇NO₃	详情	详情
(VII)	41177	(1R,5R,6S)-8-methyl-2-oxo-8-azabicyclo[3.2.1]oct-6-yl acetate		C₁₀H₁₅NO₃	详情	详情
(VIII)	41178	(1R,4S,5S,6R)-4-hydroxy-8-methyl-8-azabicyclo[3.2.1]oct-6-yl acetate		C₁₀H₁₇NO₃	详情	详情

Extended Information