|
【结 构 式】 
|
【分子编号】56116 【品名】6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one 【CA登记号】 |
【 分 子 式 】C8H7BrN2O 【 分 子 量 】227.06046 【元素组成】C 42.32% H 3.11% Br 35.19% N 12.34% O 7.05% |
合成路线1
该中间体在本合成路线中的序号：(X)Reduction of 2-aminonicotinic acid (V) by means of LiAlH4 afforded amino alcohol (VI). Subsequent bromination of (VI) with N-bromosuccinimide gave 2-amino-5-bromo-3-(hydroxymethyl)pyridine (VII). Alcohol (VII) was then converted to the bromomethyl pyridine derivative (VIII) by treatment with concentrated hydrobromic acid. Condensation of bromo amine (VIII) with dimethyl malonate led to the naphthyridine carboxylate (IX). Basic hydrolysis of the methyl ester of (IX), followed by decarboxylation under acidic conditions, gave rise to naphthyridinone (X).
| 【1】 Seefeled, M.A.; et al.; Discovery and characterization of highly potent naphthyridine-based FabI inhibitors with in vivo activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1690. |
| 【2】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 . |
| 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) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (VI) | 56112 | (2-amino-3-pyridinyl)methanol | 23612-57-9 | C6H8N2O | 详情 | 详情 |
| (VII) | 56113 | (2-amino-5-bromo-3-pyridinyl)methanol | C6H7BrN2O | 详情 | 详情 | |
| (VIII) | 56114 | 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine | 335033-38-0 | C6H6Br2N2.HBr | 详情 | 详情 |
| (IX) | 56115 | methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | 335031-10-2 | C10H9BrN2O3 | 详情 | 详情 |
| (X) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The title compound was obtained from the bromo naphthyridinone (X) by two related methods. Palladium-catalyzed Heck coupling of bromide (X) with acrylamide (IV) yielded directly the desired naphthyridinyl acrylamide. Alternatively, bromo naphthyridinone (X) was subjected to Heck coupling with tert-butyl acrylate (XI) to give adduct (XII). After acidic cleavage of the tert-butyl ester group of (XII), the resultant naphthyridinyl acrylic acid (XIII) was coupled to the indolylmethyl amine (II) to furnish the desired amide.
| 【1】 Seefeled, M.A.; et al.; Discovery and characterization of highly potent naphthyridine-based FabI inhibitors with in vivo activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1690. |
| 【2】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 56110 | N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]amine; N-methyl(2-methyl-1H-indol-3-yl)methanamine | C11H14N2 | 详情 | 详情 | |
| (IV) | 56111 | N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]acrylamide | C14H16N2O | 详情 | 详情 | |
| (X) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 | |
| (XI) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (XII) | 56117 | tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoate | C15H18N2O3 | 详情 | 详情 | |
| (XIII) | 56118 | (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoic acid | C11H10N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)2-Aminonicotinic acid (I) is reduced to alcohol (II) employing LiAlH4 in refluxing THF. Subsequent bromination of (II) with N-bromosuccinimide affords 2-amino-5-bromo-3-(hydroxymethyl)pyridine (III). Heating of alcohol (III) with concentrated HBr leads to the bromomethyl pyridine (IV). This is further condensed with dimethyl malonate in the presence of NaOMe to produce the naphthyridinecarboxylate (V). Then, alkaline hydrolysis of ester (V), followed by acidic decarboxylation gives rise to 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (VI)
| 【1】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 . |
| 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) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (II) | 56112 | (2-amino-3-pyridinyl)methanol | 23612-57-9 | C6H8N2O | 详情 | 详情 |
| (III) | 56113 | (2-amino-5-bromo-3-pyridinyl)methanol | C6H7BrN2O | 详情 | 详情 | |
| (IV) | 56114 | 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine | 335033-38-0 | C6H6Br2N2.HBr | 详情 | 详情 |
| (V) | 56115 | methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | 335031-10-2 | C10H9BrN2O3 | 详情 | 详情 |
| (VI) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)N-Methyl-(1,2,7-trimethylindol-3-ylmethyl)amine (VII) is condensed with acryloyl chloride (VIII) to form the corresponding acrylamide (IX). Then, Heck coupling between acrylamide (IX) and bromonaphthyridine (VI) in the presence of palladium acetate and tri-o-tolyl phosphine gives rise to the title compound.
| 【1】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 . |
| 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) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 | |
| (VII) | 62090 | N-methyl(1,2,7-trimethyl-1H-indol-3-yl)methanamine; N-methyl-N-[(1,2,7-trimethyl-1H-indol-3-yl)methyl]amine | C13H18N2 | 详情 | 详情 | |
| (VIII) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (IX) | 62091 | N-methyl-N-[(1,2,7-trimethyl-1H-indol-3-yl)methyl]acrylamide | C16H20N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VII)Reduction of 2-aminonicotinic acid (I) with LiAlH4 in THF gives (2-amino-3-pyridinyl)methanol (II), which by bromination with Br2 in AcOH yields (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide (III). Substitution of alcohol (III) with aqueous HBr at reflux provides the corresponding bromide (IV), which by cyclocondensation with dimethyl malonate (V) in the presence of NaH in DMF/THF provides methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (VI). Hydrolysis of ester (VI) with NaOH in refluxing MeOH, followed by decarboxylation in refluxing HCl leads to 6-bromo-3,4-dihydro-1,8-naphthyridin-2-one (VII) . Heck coupling of aryl bromide (VII) with t-butyl acrylate (VIII) in the presence of Pd(OAc)2, DIEA and P(o-tol)3 in propionitrile/DMF or acetonitrile/DMF affords the naphthyridinyl-acrylate (IX) , whose t-butyl ester group is then cleaved using TFA in CH2Cl2 to afford, after treatment with HCl in dioxane, (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (Xa) . Similarly, hydrolysis of t-butyl ester (IX) using HBr in AcOH yields 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide (Xb) . Finally, acrylic acids (Xa) or (Xb) are condensed with N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine (XI) using EDC, HOBt and DIEA in DMF .
Chlorination of 3-methylbenzofuran-2-carboxylic acid (XII) with (COCl)2 and catalytic DMF, followed by condensation with CH3NH2 in CH2Cl2 yields the corresponding benzofuran-2-carboxamide (XIII), which is finally reduced with LiAlH4 in THF .Alternatively, 3-methylbenzofuran-2-carbaldehyde (XIV) is condensed with CH3NH2 in MeOH and subsequently reduced with NaBH4 in EtOH .
| 【1】 Burgess, W.J., Huffman, W.F., Miller, W.H., Uzinskas, I.N., Jakas, D., Newlander, K.A., Seefeld, M.A. (Affinium Pharmaceuticals, Inc.). CA 2447597, EP 1560584, JP 2005519984, US 2004147580, US 7049310, US 8153652, WO 2003088897. |
| 【2】 Schmid, M.B., Mendlein, J.D., Berman, J.M., Kaplan, N. (Affinium Pharmaceuticals, Inc.). EP 1608377, JP 2006523207, US 2006142265, US 7879872, US 2012010127, WO 2004082586. |
| 【3】 Pauls, H., Ramnauth, J. (Affinium Pharmaceuticals, Inc.). EP 2125802, US 8263613, US 2013150400, WO 2008098374. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Xa) | 67798 | (E)-3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride | C11H10N2O3.HCl | 详情 | 详情 | |
| (Xb) | 67799 | 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrobromide | C11H10N2O3.HBr | 详情 | 详情 | |
| (I) | 55933 | 2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid | 5345-47-1 | C6H6N2O2 | 详情 | 详情 |
| (II) | 56112 | (2-amino-3-pyridinyl)methanol | 23612-57-9 | C6H8N2O | 详情 | 详情 |
| (III) | 67797 | (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide | 443956-55-6 | C6H72N2O.HBr | 详情 | 详情 |
| (IV) | 56114 | 5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine | 335033-38-0 | C6H6Br2N2.HBr | 详情 | 详情 |
| (V) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VI) | 56115 | methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate | 335031-10-2 | C10H9BrN2O3 | 详情 | 详情 |
| (VII) | 56116 | 6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one | C8H7BrN2O | 详情 | 详情 | |
| (VIII) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (IX) | 56117 | tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoate | C15H18N2O3 | 详情 | 详情 | |
| (XI) | 67800 | N-methyl-N-(3-methylbenzofuran-2-ylmethyl)-amine | C11H13NO | 详情 | 详情 | |
| (XII) | 67801 | 3-methylbenzofuran-2-carboxylic acid | C10H8O3 | 详情 | 详情 | |
| (XIII) | 67802 | N,3-dimethylbenzofuran-2-carboxamide | C11H11NO2 | 详情 | 详情 | |
| (XIV) | 67803 | 3-methylbenzofuran-2-carbaldehyde | C10H8O2 | 详情 | 详情 |