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【结 构 式】 
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【分子编号】10159 【品名】2,6-Dibromopyridine 【CA登记号】626-05-1 |
【 分 子 式 】C5H3Br2N 【 分 子 量 】236.89356 【元素组成】C 25.35% H 1.28% Br 67.46% N 5.91% |
合成路线1
该中间体在本合成路线中的序号：(I)A synthesis of deuterium-labeled acrivastine has been published. The reaction of 2,6-dibromopyridine (I) with butyllithium in ethyl ether gives the monolithium salt (II), which is condensed with perdeuterated 4-methylbenzaldehyde (III) in the same solvent to yield the methanol (IV). The oxidation of (IV) with pyridinium chlorochromate in dichloromethane affords the corresponding ketone (V), which is condensed with ethyl acrylate (VI) by means of palladium acetate, triphenylphosphine and tributylamine at 130 C to give 3-[6-([2H]-4-methylbenzoyl)pyridin-2-yl]acrylic acid ethyl ester (VII). The Wittig condensation of (VII) with triphenyl[2-(1-pyrrolidinyl)ethyl]phosphonium bromide (VIII) by means of butyllithium in THF affords a cis:trans mixture that is submitted to chromatography yielding the (E,E)-isomer (IX), which is finally hydrolyzed with NaOH in ethanol, at room temperature.
| 【1】 Thompson, J.B.; Blake, K.W.; McNutt, R.W.; Synthesis of deuterium-labeled acrivastine and an acrivastine metabolite. J Label Compd Radiopharm 1995, 36, 10, 973. |
| 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) | 10159 | 2,6-Dibromopyridine | 626-05-1 | C5H3Br2N | 详情 | 详情 |
| (II) | 10160 | (6-Bromo-2-pyridinyl)lithium | C5H3BrLiN | 详情 | 详情 | |
| (III) | 10161 | 4-Methylbenzaldehyde | 104-87-0 | C8H8O | 详情 | 详情 |
| (III) | 44590 | 4-methylbenzaldehyde | C8H8O | 详情 | 详情 | |
| (IV) | 10162 | (6-Bromo-2-pyridinyl)(4-methylphenyl)methanol | C13H12BrNO | 详情 | 详情 | |
| (IV) | 44591 | (6-bromo-2-pyridinyl)(4-methylphenyl)methanol | C13H12BrNO | 详情 | 详情 | |
| (V) | 10163 | (6-Bromo-2-pyridinyl)(4-methylphenyl)methanone | C13H10BrNO | 详情 | 详情 | |
| (V) | 44592 | (6-bromo-2-pyridinyl)(4-methylphenyl)methanone | C13H10BrNO | 详情 | 详情 | |
| (VI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (VII) | 10165 | ethyl (E)-3-[6-(4-methylbenzoyl)-2-pyridinyl]-2-propenoate | C18H17NO3 | 详情 | 详情 | |
| (VII) | 44593 | ethyl (E)-3-[6-(4-methylbenzoyl)-2-pyridinyl]-2-propenoate | C18H17NO3 | 详情 | 详情 | |
| (VIII) | 10166 | Triphenyl[2-(1-pyrrolidinyl)ethyl]phosphonium bromide | C24H27BrNP | 详情 | 详情 | |
| (IX) | 10167 | ethyl (E)-3-[6-[(E)-1-(4-methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl]-2-pyridinyl]-2-propenoate | C24H28N2O2 | 详情 | 详情 | |
| (IX) | 44594 | ethyl (E)-3-[6-[(E)-1-(4-methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl]-2-pyridinyl]-2-propenoate | C24H28N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)2-Amino-6-bromopyridine (II) was prepared by reaction of 2,6-dibromopyridine (I) with ammonium hydroxide in a pressure bomb at 170 C. The amino group of (III) was subsequently blocked as the pyrrole derivative (IV) by condensation with 2,5-hexanedione (III). Diazotization of p-aminophenyl ethanol (V) followed by treatment with KI gave iodo derivative (VI). Subsequent reaction of (VI) with SOCl2 provided chloride (VII). Arylpyridine (VIII) was obtained by lithiation of bromopyridine (IV) with BuLi, followed by conversion to the corresponding organozinc compound with ZnCl2 and palladium-catalyzed coupling with iodide (VII). Pyrrole ring cleavage in (VIII) upon treatment with hydroxylamine furnished aminopyridine (IX). Subsequent condensation with N-Boc-piperazine (X) provided adduct (XI). After acid cleavage of the Boc group of (XI), alkylation of the resulting piperazine with phenacyl chloride (XII) yielded the title compound. Alternatively, the title compound was obtained by condensation of chloride (IX) with N-phenacylpiperazine (XIII).
| 【1】 Qian, W.; Lowe, J.A.; Volkmann, R.A.; et al.; A new class of selective and potent inhibitors of neuronal nitric oxide synthase. Bioorg Med Chem Lett 1999, 9, 17, 2569. |
| 【2】 Lowe, J.A. III; Whittle, P.J. (Pfizer Inc.); 6-Phenylpyridyl-2-amine derivs.. EP 0891332; JP 1999510513; WO 9736871 . |
| 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) | 10159 | 2,6-Dibromopyridine | 626-05-1 | C5H3Br2N | 详情 | 详情 |
| (II) | 41341 | 2-amino-6-bromopyridine; 6-bromo-2-pyridinamine; 6-bromo-2-pyridinylamine | 19798-81-3 | C5H5BrN2 | 详情 | 详情 |
| (III) | 24848 | acetonyl acetone;1,2-Diacetylethane;a,b-Diacetylethane;2,5-Diketohexane;Diacetonyl;Acetonylacetone;2,5-Dioxohexane;2,5-hexanedione | 110-13-4 | C6H10O2 | 详情 | 详情 |
| (IV) | 41342 | 2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine | C11H11BrN2 | 详情 | 详情 | |
| (V) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (VI) | 30973 | 2-(4-iodophenyl)-1-ethanol | C8H9IO | 详情 | 详情 | |
| (VII) | 41343 | 1-(2-chloroethyl)-4-iodobenzene | C8H8ClI | 详情 | 详情 | |
| (VIII) | 41344 | 2-[4-(2-chloroethyl)phenyl]-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine | C19H19ClN2 | 详情 | 详情 | |
| (IX) | 41345 | 6-[4-(2-chloroethyl)phenyl]-2-pyridinamine; 6-[4-(2-chloroethyl)phenyl]-2-pyridinylamine | C13H13ClN2 | 详情 | 详情 | |
| (X) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XI) | 41346 | tert-butyl 4-[4-(6-amino-2-pyridinyl)phenethyl]-1-piperazinecarboxylate | C22H30N4O2 | 详情 | 详情 | |
| (XII) | 38669 | 2-chloro-1-phenyl-1-ethanone | 532-27-4 | C8H7ClO | 详情 | 详情 |
| (XIII) | 41347 | 1-phenyl-2-(1-piperazinyl)-1-ethanone | C12H16N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)N-Methylation of piperidine-4-carboxylic acid (VIII) by means of HCHO in the presence of H2 over Pd/C in H2O gives 1-methylpiperidine-4-carboxylic acid (IX), which by chlorination with (COCl)2 in the presence of DMF in refluxing CH2Cl2 furnishes 1-methylpiperidine-4-carbonyl chloride hydrochloride (X). Condensation of acid chloride (X) with Me2NH in the presence of Et3N in THF yields N,N,1-trimethylpiperidine-4-carboxamide (XI), which then condenses with 2,6-dibromopyridine (XII) in the presence of BuLi in methyl t-butyl ether (MTBE), affording (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (XIII). Amination of bromo derivative (XIII) with NH3 in the presence of Cu2O in ethylene glycol at 85 °C produces the desired intermediate (V) .
| 【1】 Kohlman, D.T., Mancuso, V., Cohen, M.P. et al. (Eli Lilly and Company). Pyridinoylpiperidines as 5-HT1F agonists. EP 1492786, JP 2005530722, JP 2010159272, US 2005222206, US 7423050, US 8044207, WO 2003084949. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 68622 | (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone | C12H17N3O | 详情 | 详情 | |
| (VIII) | 17402 | 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid | 498-94-2 | C6H11NO2 | 详情 | 详情 |
| (IX) | 68625 | 1-methyl-4-Piperidinecarboxylicacid;1-methylpiperidine-4-carboxylic acid;1-methyl-Isonipecoticacid;4-Carboxy-N-methylpiperidine;N-Methylpiperidine-4-carboxylic acid | 68947-43-3 | C7H13NO2 | 详情 | 详情 |
| (X) | 68626 | 1-methylpiperidine-4-carbonyl chloride hydrochloride | C7H12ClNO.HCl | 详情 | 详情 | |
| (XI) | 68627 | N,N,1-trimethylpiperidine-4-carboxamide | C9H18N2O | 详情 | 详情 | |
| (XII) | 10159 | 2,6-Dibromopyridine | 626-05-1 | C5H3Br2N | 详情 | 详情 |
| (XIII) | 68628 | (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone | C12H15BrN2O | 详情 | 详情 |