|
【结 构 式】 
|
【分子编号】28589 【品名】(4aR,10bR)-8-bromo-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one 【CA登记号】 |
【 分 子 式 】C15H18BrNO 【 分 子 量 】308.21806 【元素组成】C 58.45% H 5.89% Br 25.92% N 4.54% O 5.19% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reaction of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-one (I) with 1(R)-phenylethylamine (II) by means of p-toluenesulfonic acid in refluxing toluene gives the enamine (III), which is methylated with lithium diisopropylamide and methyl iodide in THF yielding the 1-methyldihydronaphthalene (IV). The cyclization of (IV) with acryloyl chloride (V) in toluene affords the benzoquinoline derivative (VI), which is treated with triethylsilane and trifluoroacetic acid to eliminate the chiral auxiliar giving intermediate (VII). The methylation of (VII) with methyllithium in THF yields the N-methyl benzoquinoline (VIII), which is treated with N,N'-diisopropylthiuram disulfide (IX) and tert-butyllithium to afford the thiol derivative (X). Finally, this compound is condensed with 2-chloro-4-ethylbenzo thiazole (XI) by means of K2CO3 in hot DMF.
| 【1】 Brennan, J.; et al.; Selective thiomethylation of benzo[f]quinolinone dianions facilitates production of a type I/II 5-alpha-reductase inhibitor (LY320236). 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst ORGN 151. |
| 【2】 Audia, J.E.; Haehl, K.L.; Kress, T.J.; McQuaid, L.A.; Neubauer, B.L.; Rocco, V.P.; Wepsiec, J.P. (Eli Lilly and Company); 5alpha-Reductase inhibitors. CA 2158609; EP 0703221; JP 1996225533; WO 9609046 . |
| 【3】 Audia, J.E.; Neubauer, B.L. (Eli Lilly and Company); Benzoquinolin-3-ones to inhibit bone loss. EP 0742010; JP 1999511739; US 5550134; WO 9635422 . |
| 【4】 Audia, J.E.; Neubauer, B.L. (Eli Lilly and Company); Use of benzoquinolin-3-ones for the treatment and prevention of prostatic cancer. CA 2172211; EP 0733365; JP 1996277220 . |
| 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) | 28584 | 6-bromo-3,4-dihydro-2(1H)-naphthalenone | 4133-35-1 | C10H9BrO | 详情 | 详情 |
| (II) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (III) | 28585 | 6-bromo-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C18H18BrN | 详情 | 详情 | |
| (IV) | 28586 | N-(6-bromo-1-methyl-3,4-dihydro-2-naphthalenyl)-N-[(1R)-1-phenylethyl]amine | C19H20BrN | 详情 | 详情 | |
| (V) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (VI) | 28587 | (10bR)-8-bromo-10b-methyl-4-[(1R)-1-phenylethyl]-1,4,6,10b-tetrahydrobenzo[f]quinolin-3(2H)-one | C22H22BrNO | 详情 | 详情 | |
| (VII) | 28588 | (4aR,10bR)-8-bromo-10b-methyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C14H16BrNO | 详情 | 详情 | |
| (VIII) | 28589 | (4aR,10bR)-8-bromo-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H18BrNO | 详情 | 详情 | |
| (IX) | 28590 | 2-[([[(isopropylamino)carbothioyl]disulfanyl]carbothioyl)amino]propane | C8H16N2S4 | 详情 | 详情 | |
| (X) | 28591 | (4aR,10bR)-4,10b-dimethyl-8-sulfanyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H19NOS | 详情 | 详情 | |
| (XI) | 28592 | 2-chloro-4-ethyl-1,3-benzothiazole | C9H8ClNS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)The reaction of 6-bromo-1,2,3,4-tetrahydronaphthalen-2-one (I) with 1,3-bis(trimethylsilyloxy)propane (II) by means of trimethylsilyl trifluoromethanesulfonate in THF gives the propylene ketal (III), which is treated with dimethyldisulfide and BuLi in THF yielding the methylsulfanyl derivative (IV). The hydrolysis of (IV) by means of HCl in THF affords 6-(methylsulfanyl)-1,2,3,4-tetrahydronaphthalen-2-one (V), which is condensed with 1(R)-phenyl ethylamine (VI) by means of p-toluenesulfonic acid in refluxing toluene giving the enamine (VII). The methylation of (VII) with lithium diisopropylamide and methyl iodide in THF yields the 1-methyldihydronaphthalene (VIII), which is cyclized with acryloyl anhydride (IX) in toluene affording the benzoquinoline derivative (X). The treatment of (X) with triethylsilane and trifluoroacetic acid to eliminate the chiral auxiliar gives intermediate (XI), which is methylated with methyllithium in THF yielding the N-methylbenzoquinoline (XII). The oxidation of (XII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane affords the corresponding methylsulfinyl derivative (XIII), which by reaction with trifluoroacetic anhydride provides the trifluoroacetoxymethylsulfanyl derivative (XIV). Finally, this compound is condensed with 2-chloro-4-ethylbenzothiazole (XV) by means of tetrabutylammonium bisulfate (BNS) and NaBH4 in toluene/water.
| 【1】 Udodong, U.E.; Brennan, J.; Doecke, C.W.; Heath, P.C.; Patterson, L.E.; Weigel, L.O. (Eli Lilly and Company); Synthesis of benzo[f]quinolinones. WO 9818757 . |
| 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) | 28584 | 6-bromo-3,4-dihydro-2(1H)-naphthalenone | 4133-35-1 | C10H9BrO | 详情 | 详情 |
| (II) | 28593 | trimethyl[5-(trimethylsilyl)pentyl]silane | C11H28Si2 | 详情 | 详情 | |
| (III) | 28594 | 6'-Bromo-1',2',3',4'-tetrahydrospiro[1,3-dioxane-2,2'-naphthalene] | C13H15BrO2 | 详情 | 详情 | |
| (IV) | 28595 | 6'-(Methylsulfanyl)-1',2',3',4'-tetrahydrospiro[1,3-dioxane-2,2'-naphthalene] | C14H18O2S | 详情 | 详情 | |
| (V) | 28596 | 6-(methylsulfanyl)-3,4-dihydro-2(1H)-naphthalenone | C11H12OS | 详情 | 详情 | |
| (VI) | 10039 | (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine | 3886-69-9 | C8H11N | 详情 | 详情 |
| (VII) | 28598 | 6-(methylsulfanyl)-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C19H21NS | 详情 | 详情 | |
| (VIII) | 28599 | 1-methyl-6-(methylsulfanyl)-N-[(1R)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine | C20H23NS | 详情 | 详情 | |
| (IX) | 28600 | acrylic anhydride | C6H6O3 | 详情 | 详情 | |
| (X) | 28601 | (10bR)-10b-methyl-8-(methylsulfanyl)-4-[(1R)-1-phenylethyl]-1,4,6,10b-tetrahydrobenzo[f]quinolin-3(2H)-one | C23H25NOS | 详情 | 详情 | |
| (XI) | 28602 | (4aR,10bR)-10b-methyl-8-(methylsulfanyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H19NOS | 详情 | 详情 | |
| (XII) | 28603 | (4aR,10bR)-4,10b-dimethyl-8-(methylsulfanyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C16H21NOS | 详情 | 详情 | |
| (XIII) | 28604 | (4aR,10bR)-4,10b-dimethyl-8-(methylsulfinyl)-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C16H21NO2S | 详情 | 详情 | |
| (XIV) | 28605 | [[(4aR,10bR)-4,10b-dimethyl-3-oxo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-8-yl]sulfanyl]methyl 2,2,2-trifluoroacetate | C18H20F3NO3S | 详情 | 详情 | |
| (XV) | 28592 | 2-chloro-4-ethyl-1,3-benzothiazole | C9H8ClNS | 详情 | 详情 | |
| (XVI) | 28597 | 2-[4-(methylsulfanyl)phenyl]acetic acid | C9H10O2S | 详情 | 详情 | |
| (XVII) | 25755 | 2-[4-(methylsulfanyl)phenyl]acetyl chloride | C9H9ClOS | 详情 | 详情 | |
| (XVIII) | 28363 | ethylene | 9002-88-4 | C2H4 | 详情 | 详情 |
| (XIX) | 28589 | (4aR,10bR)-8-bromo-4,10b-dimethyl-1,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3(2H)-one | C15H18BrNO | 详情 | 详情 |