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【结 构 式】 
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【分子编号】37020 【品名】4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid 【CA登记号】 |
【 分 子 式 】C14H19NO4S 【 分 子 量 】297.3752 【元素组成】C 56.55% H 6.44% N 4.71% O 21.52% S 10.78% |
合成路线1
该中间体在本合成路线中的序号：(IX)Condensation of 4-fluorophenylacetyl chloride (I) with ethylene in the presence of AlCl3 provided the beta-tetralone (II). After conversion of (III) into enamine (IV) upon reaction with pyrrolidine (III) in MeOH, alkylation with allyl bromide (V) afforded iminium salt (VI). Acid hydrolysis of (VI) generated the allyl tetralone (VII), which was subjected to reductive amination with ammonium acetate and sodium cyanoborohydride to produce the cis-1-allyl-2-aminotetralin (VIII) as the major isomer. Coupling of (VIII) with carboxylic acid (IX) using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) gave amide (X), which was finally reduced to the target aminotetralin derivative with LiAlH4.
| 【1】 Lovenberg, T.W.; McNally, J.J.; Youngman, M.A.; et al.; alpha-Substituted N-(sulfonamido)alkyl-beta-aminotetralins: Potent and selective neuropeptide Y Y5 receptor antagonists. J Med Chem 2000, 43, 3, 346. |
| 【2】 Reitz, A.B.; Lovenberg, T.W.; Dax, S.L.; Youngman, M.A.; McNally, J.J. (Ortho-McNeil Pharmaceutical, Inc.); N-Substd. aminotetralins as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders. WO 9955667 . |
| 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) | 37014 | 2-(4-fluorophenyl)acetyl chloride | 459-04-1 | C8H6ClFO | 详情 | 详情 |
| (II) | 37015 | 6-fluoro-3,4-dihydro-2(1H)-naphthalenone | C10H9FO | 详情 | 详情 | |
| (III) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (IV) | 37016 | 1-(6-fluoro-3,4-dihydro-2-naphthalenyl)pyrrolidine | C14H16FN | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 37017 | 1-[1-allyl-6-fluoro-3,4-dihydro-2(1H)-naphthalenylidene]pyrrolidinium bromide | C17H21BrFN | 详情 | 详情 | |
| (VII) | 37018 | 1-allyl-6-fluoro-3,4-dihydro-2(1H)-naphthalenone | C13H13FO | 详情 | 详情 | |
| (VIII) | 37019 | (1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenamine; (1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenylamine | C13H16FN | 详情 | 详情 | |
| (IX) | 37020 | 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C14H19NO4S | 详情 | 详情 | |
| (X) | 37021 | N-[(1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide | C27H33FN2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Enamine (III), prepared from beta-tetralone (I) by condensation with pyrrolidine (II) in refluxing benzene, was alkylated with bromoacetonitrile to provide, after hydrolytic treatment, keto nitrile (IV). Reductive amination of (IV) with ammonium acetate and NaBH3CN in MeOH furnished the benzo[e]indole tricyclic derivative (V), isolated as the hydrochloride salt. Coupling of (V) with trans-4-[(benzenesulfonamido) methyl]cyclohexanecarboxylic acid (VI) using O-benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU) gave amide (VII). This was finally reduced to the corresponding amine employing LiAlH4 in THF.
| 【1】 Wilson, S.J.; Dax, S.L.; Nepomuceno, D.H.; McNally, J.J.; Youngman, M.A.; Lovenverg, T.W.; N-(Sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: Potent antagonists of human neuropeptide Y Y5 receptor. Bioorg Med Chem Lett 2000, 10, 3, 213. |
| 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) | 40937 | 6-hydroxy-3,4-dihydro-2(1H)-naphthalenone | C10H10O2 | 详情 | 详情 | |
| (II) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (III) | 40938 | 6-(1-pyrrolidinyl)-7,8-dihydro-2-naphthalenol | C14H17NO | 详情 | 详情 | |
| (IV) | 40939 | 2-(6-hydroxy-2-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)acetonitrile | C12H11NO2 | 详情 | 详情 | |
| (V) | 40940 | (3aS,9bR)-2-amino-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-7-ol | C12H14N2O | 详情 | 详情 | |
| (VI) | 37020 | 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid | C14H19NO4S | 详情 | 详情 | |
| (VII) | 40941 | N-[(3aS,9bR)-7-hydroxy-3a,4,5,9b-tetrahydro-1H-benzo[e]indol-2-yl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide | C26H31N3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)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 |