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【结 构 式】 
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【分子编号】26874 【品名】methyl 2-bromo-5-nitrobenzoate 【CA登记号】6942-36-5 |
【 分 子 式 】C8H6BrNO4 【 分 子 量 】260.04398 【元素组成】C 36.95% H 2.33% Br 30.73% N 5.39% O 24.61% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of phenylboronic acid (I) with methyl 2-bromo-5-nitrobenzoate (II) by means of palladium tetrakis(triphenylphosphine) gives the biphenyl-2-carboxylic ester (III), which is treated with KOH in ethanol/THF to afford the corresponding free acid (IV). The reaction of (IV) with SOCl2 yields the acyl chloridde (V), which is cyclized by means of AlCl3 to provide the dibenzopyranone (VI). The reduction of the nitro group of (VI) with Zn and CaCl2 in refluxing ethanol gives the corresponding amino derivative (VII), which is cyclized with acetone and I2 at 125-35 C yielding the tetracyclic ketone (VIII). The reaction of (VIII) with 3-chlorophenyllithium (IX) in THF affords the tetracyclic hemiketal (X), which is dehydroxylated with boron trifluoride ethearate and triethylsilane in dichloromethane to give the target compound as a racemic mixture (XI). Finally, this racemate is optically resolved by chiral HPLC over a Whelk-O column.
| 【1】 Zhi, L.; Jones, T.K.; Schrader, W.T.; Gottardis, M.M.; Pooley, C.L.F.; West, S.J.; Tegley, C.M.; Wang, M.-W.; Pathirana, C.; Edwards, J.P.; Preparation, resolution, and biological evaluation of 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines: Potent, orally active, nonsteroidal progesterone receptor agonists. J Med Chem 1998, 41, 15, 2779. |
| 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) | 26873 | 5-fluoro-2-methoxyphenylboronic acid | C7H8BFO3 | 详情 | 详情 | |
| (II) | 26874 | methyl 2-bromo-5-nitrobenzoate | 6942-36-5 | C8H6BrNO4 | 详情 | 详情 |
| (III) | 26875 | methyl 3'-fluoro-6'-methoxy-4-nitro[1,1'-biphenyl]-2-carboxylate | C15H12FNO5 | 详情 | 详情 | |
| (IV) | 26876 | 3'-fluoro-6'-methoxy-4-nitro[1,1'-biphenyl]-2-carboxylic acid | C14H10FNO5 | 详情 | 详情 | |
| (V) | 27428 | 3'-fluoro-6'-methoxy-4-nitro[1,1'-biphenyl]-2-carbonyl chloride | C14H9ClFNO4 | 详情 | 详情 | |
| (VI) | 26877 | 2-fluoro-8-nitro-6H-benzo[c]chromen-6-one | C13H6FNO4 | 详情 | 详情 | |
| (VII) | 26878 | 8-amino-2-fluoro-6H-benzo[c]chromen-6-one | C13H8FNO2 | 详情 | 详情 | |
| (VIII) | 26879 | 9-fluoro-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one | C19H16FNO2 | 详情 | 详情 | |
| (IX) | 27429 | (3-chlorophenyl)lithium | C6H4ClLi | 详情 | 详情 | |
| (X) | 27430 | 5-(3-chlorophenyl)-9-fluoro-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C25H21ClFNO2 | 详情 | 详情 | |
| (XI) | 27431 | 5-(3-chlorophenyl)-9-fluoro-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline | C25H21ClFNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Lithiation of 2-bromo-4-fluoroanisole (I) produced the intermediate organolithium reagent (II), which was treated with trimethyl borate to yield, after acid hydrolysis, the arylboronic acid (III). Subsequent Suzuki coupling of (III) with methyl 2-bromo-5-nitrobenzoate (IV) in the presence of palladium catalyst afforded biphenyl (V). The methyl ester group of (V) was hydrolyzed with KOH to give acid (VI). This was converted to the acid chloride with SOCl2, and then cyclized to the benzocoumarin (VII) employing AlCl3. Reduction of the nitro group of (VII) by hydrogenation over Pd/C produced aniline (VIII). The required quinoline derivative (IX) was prepared by heating (VIII) with acetone and iodine in a pressure tube. Then, addition of butyllithium to the lactone function produced hemiacetal (X). This was finally reduced with triethylsilane in the presence of a protic or a Lewis acid to provide the title compound.
| 【1】 Zhi, L.; Tegley, C.M.; Edwards, J.P.; West, S.J.; Marschke, K.B.; Gottardis, M.M.; Mais, D.E.; Jones, T.K.; 5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: A novel class of nonsteroidal progesterone receptor modulators. Bioorg Med Chem Lett 1998, 8, 23, 3365. |
| 【2】 Jones, T.K.; Goldman, M.E.; Pooley, C.L.F.; Winn, D.T.; Edwards, J.E.; West, S.J.; Tegley, C.M.; Zhi, L.; Hamann, L.G.; Farmer, L.J.; Davis, R.J. (Ligand Pharmaceuticals, Inc.); Steroid receptor modulator cpds. and methods. EP 0800519; JP 1998510840; US 5688808; US 5688810; US 5693646; US 5693647; US 5696127; US 5696130; US 5696133; WO 9619458 . |
| 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) | 26871 | 2-bromo-4-fluorophenyl methyl ether | 452-08-4 | C7H6BrFO | 详情 | 详情 |
| (II) | 26872 | (5-fluoro-2-methoxyphenyl)lithium | C7H6FLiO | 详情 | 详情 | |
| (III) | 26873 | 5-fluoro-2-methoxyphenylboronic acid | C7H8BFO3 | 详情 | 详情 | |
| (IV) | 26874 | methyl 2-bromo-5-nitrobenzoate | 6942-36-5 | C8H6BrNO4 | 详情 | 详情 |
| (V) | 26875 | methyl 3'-fluoro-6'-methoxy-4-nitro[1,1'-biphenyl]-2-carboxylate | C15H12FNO5 | 详情 | 详情 | |
| (VI) | 26876 | 3'-fluoro-6'-methoxy-4-nitro[1,1'-biphenyl]-2-carboxylic acid | C14H10FNO5 | 详情 | 详情 | |
| (VII) | 26877 | 2-fluoro-8-nitro-6H-benzo[c]chromen-6-one | C13H6FNO4 | 详情 | 详情 | |
| (VIII) | 26878 | 8-amino-2-fluoro-6H-benzo[c]chromen-6-one | C13H8FNO2 | 详情 | 详情 | |
| (IX) | 26879 | 9-fluoro-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one | C19H16FNO2 | 详情 | 详情 | |
| (X) | 26880 | 5-butyl-9-fluoro-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C23H26FNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Resorcinol dimethyl ether (I) was metallated with n-butyllithium and the resultant organolithium compound (II) was treated with triisopropyl borate to provide, after acidic hydrolysis, boronic acid (III). Suzuki coupling of boronic acid (III) with methyl 5-nitro-2-bromobenzoate (IV) furnished biphenyl (V). Cleavage of the methyl ether groups of (V) with concomitant lactonization in the presence of BBr3 produced the benzocoumarin (VI), which was further O-methylated with iodomethane to afford the methyl ether (VII). The reduction of the nitro group of (VII) by catalytic hydrogenation over Pd/C gave amine (VIII). This was converted to the quinoline derivative (IX) via a modified Skraup ring annulation with acetone and a catalytic amount of iodine. Addition of the organolithium reagent (X) (prepared from 3-(methoxymethoxy)phenyl bromide) to the lactone (IX) provided the cyclic hemiketal (XI). The methoxymethyl protecting group was then cleaved under acidic conditions to afford diol (XII).
| 【1】 Coghlan, M.J.; et al.; Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: Selective derivatives with prednisolone-equivalent functional activity. J Med Chem 2001, 44, 18, 2879. |
| 【2】 Wang, A.X.; Kym, P.R.; Jones, T.K.; Kort, M.E.; Edwards, J.P.; Moore, J.L.; Elmore, S.W.; Coughlan, M.J.; Pratt, J.K. (Abbott Laboratories Inc.; Ligand Pharmaceuticals, Inc.); Glucocorticoid-selective anti-inflammatory agents. EP 1053239; WO 9941256 . |
| 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) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (II) | 49860 | (2,6-dimethoxyphenyl)lithium | C8H9LiO2 | 详情 | 详情 | |
| (III) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (IV) | 26874 | methyl 2-bromo-5-nitrobenzoate | 6942-36-5 | C8H6BrNO4 | 详情 | 详情 |
| (V) | 49861 | methyl 2',6'-dimethoxy-4-nitro[1,1'-biphenyl]-2-carboxylate | C16H15NO6 | 详情 | 详情 | |
| (VI) | 49862 | 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one | C13H7NO5 | 详情 | 详情 | |
| (VII) | 49863 | 1-methoxy-8-nitro-6H-benzo[c]chromen-6-one | C14H9NO5 | 详情 | 详情 | |
| (VIII) | 49864 | 8-amino-1-methoxy-6H-benzo[c]chromen-6-one | C14H11NO3 | 详情 | 详情 | |
| (IX) | 49865 | 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one | C20H19NO3 | 详情 | 详情 | |
| (X) | 49866 | [3-(methoxymethoxy)phenyl]lithium | C8H9LiO2 | 详情 | 详情 | |
| (XI) | 49867 | 10-methoxy-5-[3-(methoxymethoxy)phenyl]-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C28H29NO5 | 详情 | 详情 | |
| (XII) | 49868 | 5-(3-hydroxyphenyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C26H25NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Lithiation of 1,3-dimethoxybenzene (I), followed by addition of triisopropyl borate to the resultant lithio derivative (II) provided boronic acid (III). This was subjected to palladium-catalyzed Suzuki coupling with methyl 5-nitro-2-bromobenzoate (IV) to afford the biphenyl compound (V). Cleavage of the methyl ethers of (V) using boron tribromide gave rise to the tricyclic lactone (VI). After methylation of the hydroxyl group of (VI) with iodomethane and cesium carbonate, the resultant nitro derivative (VII) was reduced to amine (VIII) by catalytic hydrogenation. Iodine-catalyzed condensation of amine (VIII) with acetone at 105 ºC in a sealed vessel furnished the benzopyranoquinoline system (IX). The lactone function of (IX) was then reduced to the corresponding lactol (X) by means of DIBAL in cold dichloromethane. Subsequent treatment of (X) with methanol and p-toluenesulfonic acid produced acetal (XI). The acetal methoxy group of (XI) was finally displaced with allyl trimethylsilane (XII) in the presence of boron trifluoride etherate to furnish the title allyl derivative
| 【1】 Halbeisen, S.; Schmitt, R.; Birnbock, H.; Hopfgartner, G.; Van Marle, S.P.; Weber, C.; Single dose pharmacokinetics of bosentan in healthy man. 4th Int Conf Endothelin (April 23 1995, London) 1995, Abst P131. |
| 【2】 Wang, A.X.; Kym, P.R.; Jones, T.K.; Kort, M.E.; Edwards, J.P.; Moore, J.L.; Elmore, S.W.; Coughlan, M.J.; Pratt, J.K. (Abbott Laboratories Inc.; Ligand Pharmaceuticals, Inc.); Glucocorticoid-selective anti-inflammatory agents. EP 1053239; WO 9941256 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (I) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (II) | 49860 | (2,6-dimethoxyphenyl)lithium | C8H9LiO2 | 详情 | 详情 | |
| (III) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (IV) | 26874 | methyl 2-bromo-5-nitrobenzoate | 6942-36-5 | C8H6BrNO4 | 详情 | 详情 |
| (V) | 49861 | methyl 2',6'-dimethoxy-4-nitro[1,1'-biphenyl]-2-carboxylate | C16H15NO6 | 详情 | 详情 | |
| (VI) | 49862 | 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one | C13H7NO5 | 详情 | 详情 | |
| (VII) | 49863 | 1-methoxy-8-nitro-6H-benzo[c]chromen-6-one | C14H9NO5 | 详情 | 详情 | |
| (VIII) | 49864 | 8-amino-1-methoxy-6H-benzo[c]chromen-6-one | C14H11NO3 | 详情 | 详情 | |
| (IX) | 49865 | 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one | C20H19NO3 | 详情 | 详情 | |
| (X) | 62365 | 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C20H21NO3 | 详情 | 详情 | |
| (XI) | 62366 | 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-yl methyl ether; 5,10-dimethoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline | C21H23NO3 | 详情 | 详情 | |
| (XII) | 61128 | C4H8 | 详情 | 详情 |