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【结 构 式】 
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【分子编号】33327 【品名】3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine 【CA登记号】462-08-8 |
【 分 子 式 】C5H6N2 【 分 子 量 】94.11612 【元素组成】C 63.81% H 6.43% N 29.76% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 3,4,5-trimethoxybenzoyl chloride (I) with 3-aminopyridine (II) by means of pyridine in benzene gives 3-(3,4,5-trimethoxybenzamido)pyridine (III), which is hydrogenated with H2 over Pd/C in ethanol-water-HCl.
| 【1】 Irikura, T.; et al.; Benzoylamino substituted 1-benzoylpiperidines. US 3647805 . |
| 【2】 Irikura, T.; Kasuga, K.; New antiulcer agents. 1. Syntheses and biological activities of 1-acyl-2-, -3- and -4-substituted benzamidopiperidines. J Med Chem 1971, 14, 4, 357-361. |
| 【3】 Blancafort, P.; Castaner, J.; Dharma, A.P.; Serradell, M.N.; KU-54. Drugs Fut 1979, 4, 12, 882. |
合成路线2
该中间体在本合成路线中的序号：(I)Condensation of 3-aminopyridine (I) with benzaldehyde (II) in refluxing toluene with azeotropic removal of water produced imine (III), which was reduced to amine (IV) using ethanolic NaBH4. Subsequent alkylation of (IV) with methyl 4-bromomethyl-2-(2-methylphenyl)benzoate (V) in the presence of n-BuLi in cold THF yielded the tertiary amine (VI). Basic hydrolysis of the ester group of (VI), followed by EDC-promoted coupling of the resulting carboxylic acid (VII) with L-methionine methyl ester (VIII) afforded amide (IX). The title compound was finally obtained by saponification of the methyl ester group of (IX) by means of LiOH.
| 【1】 Wang, L.; Barr, K.J.; O'Connor, S.; et al.; Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy. J Med Chem 1999, 42, 18, 3701. |
| 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) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 35752 | N-[(Z)-benzylidene]-N-(3-pyridinyl)amine; N-[(Z)-benzylidene]-3-pyridinamine | C12H10N2 | 详情 | 详情 | |
| (IV) | 35753 | N-benzyl-N-(3-pyridinyl)amine; N-benzyl-3-pyridinamine | C12H12N2 | 详情 | 详情 | |
| (V) | 35754 | ethyl 5-(bromomethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate | C17H17BrO2 | 详情 | 详情 | |
| (VI) | 35755 | ethyl 5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylate | C29H28N2O2 | 详情 | 详情 | |
| (VII) | 35756 | 5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylic acid | C27H24N2O2 | 详情 | 详情 | |
| (VIII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (IX) | 35757 | methyl (2S)-2-[[(5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate | C33H35N3O3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Monomethyl suberate (I) is treated with isobutyl chloroformate to produce the mixed anhydride (II), which is subsequently coupled with 3-aminopyridine (III), yielding amide (IV). The methyl ester group of (IV) is finally converted to the target hydroxamate upon treatment with methanolic hydroxylamine.
| 【1】 Gilbert, J.; et al.; A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 2001, 7, 8, 2292. |
| 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) | 56374 | Methyl hydrogen octane-1,8-dioate; Monomethyl suberate; Octanedioic acid monomethyl ester; Suberic acid monomethyl ester | 3946-32-5 | C9H16O4 | 详情 | 详情 |
| (II) | 56375 | C14H24O6 | 详情 | 详情 | ||
| (III) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (IV) | 56376 | methyl 8-oxo-8-(3-pyridinylamino)octanoate | C14H20N2O3 | 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 intermediate secondary amine (IV) was prepared by condensation of 3-aminopyridine (I) with isonicotinic aldehyde (II), followed by catalytic hydrogenation of the resulting imine (III).
| 【1】 Kubota, H.; Suzumura, K.; Suzuki, T.; Ohmizu, H.; Kashimura, Y.; Antioxidative property of T-0970, a new ureidophenol derivative. Free Radical Research 2000, 32, 3, 255. |
| 【2】 Suzuki, T.; Ohmizu, H.; Hashimura, Y.; Kubota, H.; Tanaka, K. (Tanabe Seiyaku Co., Ltd.); Phenol-derivs. having pharmaceutical activity and process for preparing the same. EP 0790240; JP 1998195037; US 5849732 . |
| 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) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 41431 | N-[(Z)-4-pyridinylmethylidene]-3-pyridinamine; N-(3-pyridinyl)-N-[(Z)-4-pyridinylmethylidene]amine | C11H9N3 | 详情 | 详情 | |
| (IV) | 41432 | N-(3-pyridinyl)-N-(4-pyridinylmethyl)amine; N-(4-pyridinylmethyl)-3-pyridinamine | C11H11N3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The cyclization of 3aminopyridine (I) with diethyl ethoxymethylenemalonate (II) in refluxing Dowtherm gives 4-hydroxy-1,5-naphthyridine-3-carboxylic acid ethyl ester (III), which is hydrolyzed with NaOH in refluxing water to yield the corresponding hydroxyacid (IV). The decarboxylation of (IV) by heating at 320 C in mineral oil affords 4-hydroxy-1,5-naphthyridine (V), which is acylated with trifluoromethanesulfonic anhydride to provide the triflate (VI). The reaction of (VI) with propylamine in pyridine affords 4-amino-1,5-naphthyridine (VII), which is condensed with 2-methylbenzoxazole-6-ylcarbonyl azide (VIII) (obtained by reaction of the corresponding acid (IX) with DPPA) in refluxing toluene to provide the target urea.
| 【1】 Porter, R.A.; et al.; 1,3-Biarylureas as selective non-peptide antagonists of the orexin-1 receptor. Bioorg Med Chem Lett 2001, 11, 14, 1907. |
| 【2】 Adams, J.T.; et al.; Synthesis of antimalarials. VI. Synthesis of certain 1,5- and 1,8-naphthyridine derivatives. J Am Chem Soc 1946, 68, 1317. |
| 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) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 53616 | ethyl 4-hydroxy[1,5]naphthyridine-3-carboxylate | 13801-51-9 | C11H10N2O3 | 详情 | 详情 |
| (IV) | 43932 | 4-hydroxy[1,5]naphthyridine-3-carboxylic acid | C9H6N2O3 | 详情 | 详情 | |
| (V) | 43933 | [1,5]naphthyridin-4-ol | C8H6N2O | 详情 | 详情 | |
| (VI) | 53617 | [1,5]naphthyridin-4-yl trifluoromethanesulfonate | n/a | C9H5F3N2O3S | 详情 | 详情 |
| (VII) | 43935 | [1,5]naphthyridin-4-amine; [1,5]naphthyridin-4-ylamine | C8H7N3 | 详情 | 详情 | |
| (VIII) | 53618 | 2-methyl-1,3-benzoxazole-6-carbonyl azide | n/a | C9H6N4O2 | 详情 | 详情 |
| (IX) | 43936 | 2-methyl-1,3-benzoxazole-6-carboxylic acid | C9H7NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The condensation between 4-hydroxy-3-methoxy-5-methylbenzaldehyde (I) and 3-aminopyridine (II) yields the corresponding benzalimine (III). The phenolic hydroxyl group of (III) is then protected as the silyl ether (IV) by using t-butyldimethylsilyl chloride and imidazole. Condensation of imine (IV) with the lithium derivative of diethyl methylphosphonate (V) affords the beta-amino phosphonate (VI). Finally, desilylation of (VI) with tetrabutylammonium fluoride and acetic acid provides the target phenol.
| 【1】 Phan, H.T.; et al.; Synthesis of a new series of compounds with lipoprotein(a)-lowering activity, Part 3: beta-Substituted-beta-amino-ethylphosphonates. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Ife, R.J.; Nguyen, L.M.; Bentzen, C.L.; Diep, V.V.; Azoulay, R.; Phan, H.T.; Niesor, E.J. (Ilex Oncology Research-Europe SA); beta-Substd. beta-aminoethyl phosphonates. US 2002111488; WO 0234756 . |
| 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) | 43812 | 1-(6-methoxy-2-naphthyl)-1-ethanone | 3900-45-6 | C13H12O2 | 详情 | 详情 |
| (II) | 33327 | 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine | 462-08-8 | C5H6N2 | 详情 | 详情 |
| (III) | 58411 | 2-methoxy-6-methyl-4-[(3-pyridinylimino)methyl]phenol | C14H14N2O2 | 详情 | 详情 | |
| (IV) | 58412 | N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-N-(3-pyridinyl)amine; N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-3-pyridinamine | C20H28N2O2Si | 详情 | 详情 | |
| (V) | 38496 | diethyl methylphosphonate | 683-08-9 | C5H13O3P | 详情 | 详情 |
| (VI) | 58413 | diethyl 2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)-2-(3-pyridinylamino)ethylphosphonate | C25H41N2O5PSi | 详情 | 详情 |