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【结 构 式】 
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【分子编号】12911 【品名】3-Hydroxypyridine; 3-Pyridinol 【CA登记号】109-00-2 |
【 分 子 式 】C5H5NO 【 分 子 量 】95.10084 【元素组成】C 63.15% H 5.3% N 14.73% O 16.82% |
合成路线1
该中间体在本合成路线中的序号：(II)3-Phenoxypyridine can be prepared by two different ways: 1) By reaction of 3-hydroxypyridine (I) with bromobenzene (II) by means of KOH and copper bronze at 150 C. 2) By reaction of 3-iodopyridine (III) with phenol (IV) by means of KOH and copper bronze at 150 C. The monosulfate salt is prepared by treating 3-phenoxypyridine with H2SO4.
| 【1】 Renshaw, R.R.; Conn, R.C.; Quaternary deivation of pyridyl ethers. Onium Compound. XVI. J Am Chem Soc 1937, 59, 297-301. |
| 【2】 Butler, D.E. (Pfizer Inc.); 3-Phenoxypyridine monosulfate and a method for its production. BE 0861649; DE 2755016; ES 464922; FR 2392009; GB 1559918; JP 53077068; US 4128555 . |
| 【3】 Owen, R.T.; Castaner, J.; Serradell, M.N.; CI-844. Drugs Fut 1985, 10, 4, 279. |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of 3-hydroxypyridine (I) first with formaldehyde and NaOH in water, and then with benzyl bromide (A) in ethanol gives 3-benzyloxy-2,6-bis(hydroxymethyl)pyridine hydrochloride (II), which is oxidized with MnO2 in refluxing benzene yielding 2-hydroxmethyl-3-benzyloxy-6-pyridincarboxaldehyde (III). The condensation of (III) with tertbutylisonitrile (B) and acetic acid in refluxing CHCl3 affords N-tertbutyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridil)-2-acetoxyacetamide (IV), which is hydrolyzed with 12N HCl yielding N-tertbutyl-2-(5-benzyloxy-6-hydroxymethyl-2-pyridil)-2-hydroxyacetamide (V). The reduction of the amide group of (V) with diborane in THF gives 2-hydroxymethyl-3-benzyloxy-6-(1-hydroxy-2-tertbutylaminoethyl)pyridine (VI), which is finally debenzylated with H2 over Pd/C in methanol.
| 【1】 Barth, W.; 2-Hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines. DE 2204195; FR 2125309; GB 1367668; GB 1367669; US 3700681; US 3763173 . |
| 【2】 Castaner, J.; Thorpe, P.; Pirbuterol. Drugs Fut 1977, 2, 1, 60. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (B) | 33871 | pivalonitrile | 630-18-2 | C5H9N | 详情 | 详情 |
| (I) | 12911 | 3-Hydroxypyridine; 3-Pyridinol | 109-00-2 | C5H5NO | 详情 | 详情 |
| (II) | 33869 | [3-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]methanol | C14H15NO3 | 详情 | 详情 | |
| (III) | 33870 | 5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinecarbaldehyde | C14H13NO3 | 详情 | 详情 | |
| (IV) | 33872 | 1-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-2-(tert-butylamino)-2-oxoethyl acetate | C21H26N2O5 | 详情 | 详情 | |
| (V) | 33873 | 2-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-N-(tert-butyl)-2-hydroxyacetamide | C19H24N2O4 | 详情 | 详情 | |
| (VI) | 33874 | 1-[5-(benzyloxy)-6-(hydroxymethyl)-2-pyridinyl]-2-(tert-butylamino)-1-ethanol | C19H26N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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.
| 【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4
该中间体在本合成路线中的序号：(I)The reaction of 3-hydroxypyridine (I) with (S)-glycidol 3-nitrobenzenesulfonate (II) by means of sodium hexamethyldisylazide in DMSO gives 2(S)-(3-pyridyloxymethyl)oxirane (III), which is condensed with 2-(4-nitrophenyl)ethylamine (IV) by means of triethylamine in refluxing methanol yielding the chiral isopropanol (V). The protection of the secondary amino group of (V) with tert-butoxycarbonyl anhydride affords the carbamate (VI), which is submitted to reduction at the nitro group with H2 over palladium hydroxide in ethyl acetate providing the aniline derivative (VII). The acylation of (VII) with 4-iodobenzenesulfonyl chloride (VIII) and pyridine in dichloromethane affords the sulfonamide (IX), which is finally deprotected with 6N HCl in methanol.
| 【1】 Fisher, M.H.; Mathvink, R.J.; Ok, H.O.; Parmee, E.R.; Weber, A.E. (Merck & Co., Inc.); Substd. phenyl sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. CA 2114712; EP 0611003; JP 1995010827; US 5451677; WO 9418161 . |
| 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) | 16259 | (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate | 115314-14-2 | C9H9NO6S | 详情 | 详情 |
| (III) | 27807 | (2S)oxiranylmethyl 3-pyridinyl ether | C8H9NO2 | 详情 | 详情 | |
| (IV) | 26560 | 4-nitrophenethylamine | 24954-67-4 | C8H10N2O2 | 详情 | 详情 |
| (V) | 27808 | (2S)-1-[(4-nitrophenethyl)amino]-3-(3-pyridinyloxy)-2-propanol | C16H19N3O4 | 详情 | 详情 | |
| (VI) | 27809 | tert-butyl (2S)-2-hydroxy-3-(3-pyridinyloxy)propyl(4-nitrophenethyl)carbamate | C21H27N3O6 | 详情 | 详情 | |
| (VII) | 27810 | tert-butyl 4-aminophenethyl[(2S)-2-hydroxy-3-(3-pyridinyloxy)propyl]carbamate | C21H29N3O4 | 详情 | 详情 | |
| (VIII) | 27811 | 4-iodobenzenesulfonyl chloride | 98-61-3 | C6H4ClIO2S | 详情 | 详情 |
| (IX) | 27812 | tert-butyl (2S)-2-hydroxy-3-(3-pyridinyloxy)propyl(4-[[(4-iodophenyl)sulfonyl]amino]phenethyl)carbamate | C27H32IN3O6S | 详情 | 详情 |