【结 构 式】 |
【药物名称】Lecozotan Hydrochloride, SRA-333 【化学名称】4-Cyano-N-[2(R)-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propyl]-N-(2-pyridyl)benzamide hydrochloride 【CA登记号】433282-68-9, 434283-16-6 (free base) 【 分 子 式 】C28H30ClN5O3 【 分 子 量 】520.036 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT1A Antagonists |
合成路线1
The intermediate dimesylate (VI) can be obtained as follows: The condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with ethyl bromoacetate (II) by means of Hunig's base and NaI in refluxing toluene gives the tertiary amine (III), which is reduced by means of LiAlH4 in THF to yield the diethanolamine (IV). Finally, this compound is esterified by means of mesyl chloride (V) to provide the desired dimesylate intermediate (VI). Alternatively, the diethanolamine (IV) can be obtained by direct condensation of 2,3-dihydro-1,4-benzodioxin-5-amine (I) with 2-chloroethanol (VII) by means of Hunig's base.
【1】 Jirkovsky, I.; Zeldis, J.; Chan, A.W.-Y.; Fiegelson, G.B. (Wyeth); Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines. WO 0378396 . |
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) | 22000 | 2,3-dihydro-1,4-benzodioxin-5-amine; 2,3-dihydro-1,4-benzodioxin-5-ylamine; 5-Amino-1,4-benzodioxane | 16081-46-2 | C8H9NO2 | 详情 | 详情 |
(II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
(III) | 64784 | ethyl 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-ethoxy-2-oxoethyl)amino]acetate | C16H21NO6 | 详情 | 详情 | |
(IV) | 64785 | 2-[2,3-dihydro-1,4-benzodioxin-5-yl(2-hydroxyethyl)amino]-1-ethanol | C12H17NO4 | 详情 | 详情 | |
(V) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
(VI) | 64786 | 2-(2,3-dihydro-1,4-benzodioxin-5-yl{2-[(methylsulfonyl)oxy]ethyl}amino)ethyl methanesulfonate | C14H21NO8S2 | 详情 | 详情 | |
(VII) | 10384 | 2-Chloro-1-ethanol; Ethylene chlorohydrin | 107-07-3 | C2H5ClO | 详情 | 详情 |
合成路线2
The reaction of 5(S)-methyl-3-phenyl-4,5-dihydro-3H-1,2,3-oxathiazol (VIII) with benzhydrylamine (IX) gives the sulfamic acid (X), which is deprotected by hydrogenation with H2 over Pd/C to yield N-(2(R)-aminopropyl-N-(2-pyridyl)sulfamic acid (XI). The hydrolysis of (XI) with 3N HCl affords N1-(2-pyridyl)propane-1,2(R)-diamine (XII). The cyclization of the intermediate dimesylate (VI) with sulfamic acid (XI) or diamine (XII) by means of K2CO3 and NaI in hot DMF or refluxing acetonitrile provides the disubstituted piperazine (XIII) (1), which is finally condensed with 4-cyanobenzoyl chloride (XIV) by means of K2CO3 in ethyl acetate to give the target benzamide (1,2).
【1】 Kelly, M.G.; Childers, W.E.; Rosenzweig-Lipson, S.J. (Wyeth); Serotonergic agents. US 2002107254; US 6469007; WO 0244142 . |
【2】 Jirkovsky, I.; Zeldis, J.; Chan, A.W.-Y.; Fiegelson, G.B. (Wyeth); Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines. WO 0378396 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 64786 | 2-(2,3-dihydro-1,4-benzodioxin-5-yl{2-[(methylsulfonyl)oxy]ethyl}amino)ethyl methanesulfonate | C14H21NO8S2 | 详情 | 详情 | |
(VIII) | 64787 | (5S)-5-methyl-3-(2-pyridinyl)-1,2lambda~6~,3-oxathiazolidine-2,2-dione | C8H10N2O3S | 详情 | 详情 | |
(IX) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
(X) | 64788 | (2R)-2-(benzhydrylamino)propyl(2-pyridinyl)sulfamic acid | C21H23N3O3S | 详情 | 详情 | |
(XI) | 64789 | (2R)-2-aminopropyl(2-pyridinyl)sulfamic acid | C8H13N3O3S | 详情 | 详情 | |
(XII) | 64790 | N-[(2R)-2-aminopropyl]-N-(2-pyridinyl)amine; (2R)-N~1~-(2-pyridinyl)-1,2-propanediamine | C8H13N3 | 详情 | 详情 | |
(XIII) | 64791 | N-{(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl}-2-pyridinamine; N-{(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl}-N-(2-pyridinyl)amine | C20H26N4O2 | 详情 | 详情 | |
(XIV) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |