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【结 构 式】 
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【分子编号】47507 【品名】methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine 【CA登记号】 |
【 分 子 式 】C15H19NO 【 分 子 量 】229.322 【元素组成】C 78.56% H 8.35% N 6.11% O 6.98% |
合成路线1
该中间体在本合成路线中的序号：(III)The condensation of 6-methoxy-2-tetralone (I) with pyrrolidine (II) in methanol gives the enamine (III), which is treated with 2-bromoacetonitrile (IV) to yield the pyrrolidinium salt (V). The hydrolysis of (V) with acetic acid in dichloromethane/methanol affords 2-(2-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)acetonitrile (VI), which is cyclized with ammonium acetate and NaBH3CN in refluxing methanol to provide the benzoindole derivative (VII). The condensation of (VII) with trans-4-(phenylsulfonamidomethyl)cyclohexanecarboxylic acid (VIII) by means of HBTU and DIEA in DMF gives the corresponding amide (IX), which is reduced with LiAlH4 in THF to yield the secondary amine (X). Finally, this compound is demethylated by means of BBr3 in dichloromethane.
| 【1】 Dax, S.; McNally, J. (Ortho-McNeil Pharmaceutical, Inc.); 3a,4,5,9b-Tetrahydro-1H-benz[e]indol-2-yl amine-derived neuropeptide Y receptor ligands useful in the treatment of obesity and other disorders. WO 0068197 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (IV) | 31883 | 2-bromoacetonitrile | 590-17-0 | C2H2BrN | 详情 | 详情 |
| (V) | 47508 | 1-[1-(cyanomethyl)-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]pyrrolidinium | C17H21N2O | 详情 | 详情 | |
| (VI) | 47509 | 2-(6-methoxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)acetonitrile | C13H13NO2 | 详情 | 详情 | |
| (VII) | 47510 | (3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-amine; (3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-ylamine | C13H16N2O | 详情 | 详情 | |
| (VIII) | 37020 | 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C14H19NO4S | 详情 | 详情 | |
| (IX) | 47511 | N-[(3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide | C27H33N3O4S | 详情 | 详情 | |
| (X) | 47512 | N-[[4-([[(3aS,9bR)-7-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]amino]methyl)cyclohexyl]methyl]benzenesulfonamide | C27H35N3O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)6-Methoxy-2-tetralone (I) was condensed with pyrrolidine (II) to produce enamine (III). Alkylation of (III) with benzyl bromide, followed by hydrolysis of the enamine function, furnished the 1-benzylnaphthalenone (IV). After formation of the chiral enamine (VI) with (S)-alpha-methylbenzylamine (V), enantioselective Michael addition of methyl vinyl ketone (VII) provided the (R)-diketone (VIII), which underwent ring closure to the phenanthrene derivative (IX) upon treatment with NaOMe. Methyl ether cleavage by using boron trichloride in the presence of tetrabutylammonium iodide afforded phenol (X). The conjugated ketone system of (X) was diastereoselectively reduced to the trans-phenanthrenone (XI) by means of lithium in liquid ammonia. Addition of the lithium acetylide of propyne (XII) to the ketone (XI) produced a diastereomeric mixture of carbinols from which the desired isomer (XIII) was isolated by flash chromatography. The phenol group of (XIII) was then converted to the aryl triflate (XIV) by reaction with trifluoromethanesulfonic anhydride and 2,6-lutidine.
| 【1】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (IV) | 51596 | 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone | C18H18O2 | 详情 | 详情 | |
| (V) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (VI) | 51597 | 1-benzyl-6-methoxy-N-[(1S)-1-phenylethyl]-3,4-dihydro-2-naphthalenamine; N-(1-benzyl-6-methoxy-3,4-dihydro-2-naphthalenyl)-N-[(1S)-1-phenylethyl]amine | C26H27NO | 详情 | 详情 | |
| (VII) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (VIII) | 51598 | (1R)-1-benzyl-6-methoxy-1-(3-oxobutyl)-3,4-dihydro-2(1H)-naphthalenone | C22H24O3 | 详情 | 详情 | |
| (IX) | 51599 | (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C22H22O2 | 详情 | 详情 | |
| (X) | 51600 | (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C21H20O2 | 详情 | 详情 | |
| (XI) | 51601 | (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone | C21H22O2 | 详情 | 详情 | |
| (XII) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 | |
| (XIII) | 51603 | (2R,4aS,10aR)-4a-benzyl-2-(1-propynyl)-1,2,3,4,4a,9,10,10a-octahydro-2,7-phenanthrenediol | C24H26O2 | 详情 | 详情 | |
| (XIV) | 51604 | (4bS,7R,8aR)-4b-benzyl-7-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl trifluoromethanesulfonate | C25H25F3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)6-Methoxy-2-tetralone (I) is converted into enamine (II) by treatment with pyrrolidine in toluene by azeotropic removal of water. Alkylation of (II) with benzyl bromide, followed by hydrolysis of the enamine, provides the 1-benzyl tetralone (III). This is then condensed with (S)-alpha-methylbenzylamine (IV), and the resultant imine (V) is treated with methyl vinyl ketone (VI) to furnish, after hydrolysis of the chiral auxiliary, the tricyclic ketone (VII). Rearrangement of (VII) in the presence of NaOMe results in the phenanthrenone (VIII). Cleavage of the methyl ether of (VIII) is accomplished by treatment with boron trichloride and tetrabutylammonium iodide to form phenol (IX). Reduction of enone (IX) with lithium metal in liquid ammonia leads to the saturated ketone (X). Finally, addition of the lithium acetylide of propyne (XI) to the ketone (X) affords the title carbinol adduct.
| 【1】 Morgan, B.P.; Swick, A.G.; Hargrove, D.M.; LaFlamme, J.A.; Moynihan, M.S.; Carroll, R.S.; Martin, K.A.; Lee, E.; Decosta, D.; Bordner, J.; Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J Med Chem 2002, 45, 12, 2417. |
| 【2】 Liu, K.K.-C.; Morgan, B.P.; Dow, R.L.; Swick, A.G. (Pfizer Inc.); Glucocorticoid receptor modulators. EP 1175383; WO 0066522 . |
| 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) | 47506 | 6-Methoxy-2-tetralone; 6-methoxy-3,4-dihydro-2(1H)-naphthalenone | 2472-22-2 | C11H12O2 | 详情 | 详情 |
| (II) | 47507 | methyl 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenyl ether; 1-(6-methoxy-3,4-dihydro-2-naphthalenyl)pyrrolidine | C15H19NO | 详情 | 详情 | |
| (III) | 51596 | 1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenone | C18H18O2 | 详情 | 详情 | |
| (IV) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (V) | 61649 | (1S)-N-[1-benzyl-6-methoxy-3,4-dihydro-2(1H)-naphthalenylidene]-1-phenyl-1-ethanamine | C26H27NO | 详情 | 详情 | |
| (VI) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (VII) | 61650 | (1R)-1-benzyl-10-hydroxy-5-methoxy-10-methyltricyclo[7.3.1.0~2,7~]trideca-2,4,6-trien-13-one | C22H24O3 | 详情 | 详情 | |
| (VIII) | 51599 | (4aS)-4a-benzyl-7-methoxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C22H22O2 | 详情 | 详情 | |
| (IX) | 51600 | (4aS)-4a-benzyl-7-hydroxy-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone | C21H20O2 | 详情 | 详情 | |
| (X) | 51601 | (4aS,10aR)-4a-benzyl-7-hydroxy-3,4,4a,9,10,10a-hexahydro-2(1H)-phenanthrenone | C21H22O2 | 详情 | 详情 | |
| (XI) | 51602 | 1-Propyne | C3H4 | 详情 | 详情 |