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【结 构 式】 
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【分子编号】19678 【品名】6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine 【CA登记号】1824-81-3 |
【 分 子 式 】C6H8N2 【 分 子 量 】108.143 【元素组成】C 66.64% H 7.46% N 25.9% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of ethyl chloroacetate (I) with ethyl formate (II) by means of potassium tert-butoxide in diisopropyl ether gives the 2-formylchloroacetate (III), which is cyclized with 6-methylpyridine-2-amine (IV) by means of conc. H2SO4, yielding 5-methylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (V). The chlorination of (V) with NCS in THF affords the chloromethyl derivative (VI), which is condensed with the monoprotected diamine (VII) by means of TEA to provide the adduct (VIII). The cyclization of (VIII) by means of NaOMe, TEA and NaI in DMF gives 4-[4-(benzyloxycarbonylamino)butyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one (IX), which is deprotected with H2 over Pd/C in MeOH, yielding the butylamine derivative (X). Finally, this compound is sulfonated with N-phenyltrifluoromethylsulfonimide (XI) and TEA in DMF.
| 【1】 Ikemoto, T.; et al.; A practical synthesis of the chronic renal disease agent, 4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one derivatives, using regioselective chlorination of ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxy with N-chlorosuccinimide. Tetrahedron 2000, 56, 40, 7915. |
| 【2】 Takatani, M.; Shibouta, Y.; Tomimatsu, K.; Kawamoto, T. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0771319; JP 1996081467; WO 9602542 . |
| 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) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (II) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (III) | 16600 | ethyl 2-chloro-3-oxopropanoate | C5H7ClO3 | 详情 | 详情 | |
| (IV) | 19678 | 6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine | 1824-81-3 | C6H8N2 | 详情 | 详情 |
| (V) | 42075 | ethyl 5-methylimidazo[1,2-a]pyridine-3-carboxylate | C11H12N2O2 | 详情 | 详情 | |
| (VI) | 42076 | ethyl 5-(chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate | C11H11ClN2O2 | 详情 | 详情 | |
| (VII) | 42077 | benzyl 4-aminobutylcarbamate | 62146-62-7 | C12H18N2O2 | 详情 | 详情 |
| (VIII) | 42078 | ethyl 5-[[(4-[[(benzyloxy)carbonyl]amino]butyl)amino]methyl]imidazo[1,2-a]pyridine-3-carboxylate | C23H28N4O4 | 详情 | 详情 | |
| (IX) | 42079 | benzyl 4-(3-oxo-3,5-dihydro-4H-1,4,8b-triazaacenaphthylen-4-yl)butylcarbamate | C21H22N4O3 | 详情 | 详情 | |
| (X) | 42080 | 4-(4-aminobutyl)-4,5-dihydro-3H-1,4,8b-triazaacenaphthylen-3-one | C13H16N4O | 详情 | 详情 | |
| (XI) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Bromination of 6-aminopicoline (I) in aqueous H2SO4 gave bromopyridine (II), which was subsequently nitrated in cold H2SO4 to afford (III). Reduction of the nitro group of (III) with iron powder and HCl provided diamine (IV). The imidazopyridine system (VI) was then synthesized by condensation of (IV) with valeric acid (V) in polyphosphoric acid at 110 C. Alkylation of (VI) with the biphenylmethyl bromide (VII) in the presence of K2CO3 in DMF gave (VIII), which was coupled in turn with 2-(tri-n-butylstannyl)pyridine (IX) in the presence of Pd(PPh3)4 to produce the 6-(2-pyridinyl)-imidazopyridine derivative (X). Further oxidation of (X) with meta-chloroperbenzoic acid yielded the N-oxide (XI). Finally, deprotection of the tetrazole by treatment with methanolic HCl provided the target compound.
| 【1】 Kim, N.J.; Seo, H.W.; Lee, S.H.; Shin, W.S.; Yi, K.Y.; Yoo, S.E.; Chan, O.J.; Jung, Y.S.; Lee, H.S.; Shin, Y.A.; Lee, B.H.; Kim, H.R.; Kim, S.J.; Suh, J.H. (Korea Research Institute of Chemical Technology); Pyridyl imidazole derivs. and processes for the preparation thereof. WO 9534564 . |
| 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) | 19678 | 6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine | 1824-81-3 | C6H8N2 | 详情 | 详情 |
| (II) | 18337 | 5-bromo-6-methyl-2-pyridinamine; 5-bromo-6-methyl-2-pyridinylamine; 6-AMINO-3-BROMO-2-METHYLPYRIDINE | 42753-71-9 | C6H7BrN2 | 详情 | 详情 |
| (III) | 19680 | 5-bromo-6-methyl-3-nitro-2-pyridinamine; 5-bromo-6-methyl-3-nitro-2-pyridinylamine | C6H6BrN3O2 | 详情 | 详情 | |
| (IV) | 19681 | 2-amino-5-bromo-6-methyl-3-pyridinylamine; 5-bromo-6-methyl-2,3-pyridinediamine | C6H8BrN3 | 详情 | 详情 | |
| (V) | 19682 | pentanoic acid | 109-52-4 | C5H10O2 | 详情 | 详情 |
| (VI) | 19683 | 6-bromo-2-butyl-5-methyl-1H-imidazo[4,5-b]pyridine | C11H14BrN3 | 详情 | 详情 | |
| (VII) | 19684 | 1-[5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1H-1,2,3,4-tetraazol-1-yl]ethyl ethyl ether; 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(1-ethoxyethyl)-1H-1,2,3,4-tetraazole | C18H19BrN4O | 详情 | 详情 | |
| (VIII) | 19685 | 6-bromo-2-butyl-3-([2'-[1-(1-ethoxyethyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-5-methyl-3H-imidazo[4,5-b]pyridine; 1-(5-[4'-[(6-bromo-2-butyl-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl][1,1'-biphenyl]-2-yl]-1H-1,2,3,4-tetraazol-1-yl)ethyl ethyl ether | C29H32BrN7O | 详情 | 详情 | |
| (IX) | 19686 | (2-pyridyl)tributyltin;2-(tributylstannyl)pyridine;(2-Pyridinyl)tributylstannane;2-(1,1,1-Tributylstannyl)pyridine;2-(Tri-n-butylstannyl)pyridine;2-(Tributylstannyl)pyridine;2-(Tributyltin)pyridine;2-Pyridyltri-n-butyltin;2-Pyridyltributylstannane;2-Pyridyltributyltin;Tri-n-butyl(2-pyridyl)tin;Tri-n-butyl-2-pyridylstannane;Tributyl(pyridin-2-yl)stannane;Tributyl-2-pyridylstannane;Tributyl-2-pyridyltin | 17997-47-6 | C17H31NSn | 详情 | 详情 |
| (X) | 19687 | 2-butyl-3-([2'-[1-(1-ethoxyethyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-5-methyl-6-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine; 1-[5-(4'-[[2-butyl-5-methyl-6-(2-pyridinyl)-3H-imidazo[4,5-b]pyridin-3-yl]methyl][1,1'-biphenyl]-2-yl)-1H-1,2,3,4-tetraazol-1-yl]ethyl ethyl ether | C34H36N8O | 详情 | 详情 | |
| (XI) | 19688 | 2-[2-butyl-3-([2'-[1-(1-ethoxyethyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl)-5-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-1-pyridiniumolate | C34H36N8O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II). Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity. After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine, (IV) was obtained, then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C. The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI). Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound, which was finally deprotected by treatment with HCl in MeOH-dioxan.
| 【1】 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514. |
| 【2】 Trussardi, R.; Karpf, M. (F. Hoffmann-La Roche AG); Process for the preparation of mixed anhydrides. EP 0847994 . |
| 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) | 16585 | benzyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C17H19NO3 | 详情 | 详情 | |
| (II) | 16586 | benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate | C17H17NO3 | 详情 | 详情 | |
| (III) | 19678 | 6-methyl-2-pyridinamine; 6-methyl-2-pyridinylamine; 6-amino-2-picoline; 2-Amino-6-methylpyridine | 1824-81-3 | C6H8N2 | 详情 | 详情 |
| (IV) | 19920 | benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylcarbamate | C46H64N2O8Si2 | 详情 | 详情 | |
| (V) | 19921 | (1R,2S,3S,4R)-4-amino-1-benzyl-5-phenyl-2,3-bis[[2-(trimethylsilyl)ethoxy]methoxy]pentylamine; (2R,3S,4S,5R)-1,6-diphenyl-3,4-bis[[2-(trimethylsilyl)ethoxy]methoxy]-2,5-hexanediamine | C30H52N2O4Si2 | 详情 | 详情 | |
| (VI) | 19922 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one | C31H50N2O5Si2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The title diaryl thiazolidinone was synthesized by condensation between 2,6-dichlorobenzaldehyde (I), 2-amino-6-methylpyridine (II) and mercaptoacetic acid (III) in refluxing toluene.
| 【1】 Barreca, M.L.; et al.; Discovery of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV-1 agents. Bioorg Med Chem Lett 2001, 11, 13, 1793. |