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【结 构 式】 
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【分子编号】37014 【品名】2-(4-fluorophenyl)acetyl chloride 【CA登记号】459-04-1 |
【 分 子 式 】C8H6ClFO 【 分 子 量 】172.5861432 【元素组成】C 55.68% H 3.5% Cl 20.54% F 11.01% O 9.27% |
合成路线1
该中间体在本合成路线中的序号：(XXII)Alternatively (XVII) can be obtained as follows: Reaction of 4-fluorophenyl acetic (X) with thionyl chloride in toluene in the presence of DMF provides 4-fluorophenyl acetyl chloride (XXII), which is treated with bromine and light irradiation followed by reaction with methanol to furnish methyl bromoacetate derivative (XXIII). Treatment of (XXIII) with benzyl triethylammonium chloride (XXIV) and NaN3 in MeOH followed by hydrogenation over Pd/C in MeOH gives methyl glycine derivative (XXV) in a racemic mixture, from which (XVII) is obtained by crystallization of the corresponding dibenzoyl tartaric (DBT) salts followed by salt hydrolysis by means of refluxing HCl.
| 【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211. |
| 【2】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 . |
| 【3】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 18999 | 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid | 405-50-5 | C8H7FO2 | 详情 | 详情 |
| (XVII) | 43098 | (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid | 7292-73-1 | C8H8FNO2 | 详情 | 详情 |
| (XXII) | 37014 | 2-(4-fluorophenyl)acetyl chloride | 459-04-1 | C8H6ClFO | 详情 | 详情 |
| (XXIII) | 44191 | methyl 2-bromo-2-(4-fluorophenyl)acetate | C9H8BrFO2 | 详情 | 详情 | |
| (XXIV) | 31937 | Triethylbenzylammonium chloride; N-benzyl-N,N-diethyl-1-ethanaminium chloride; Benzyltriethylammonium chloride | 56-37-1 | C13H22ClN | 详情 | 详情 |
| (XXV) | 44192 | methyl 2-amino-2-(4-fluorophenyl)acetate | C9H10FNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(II)4-Fluorophenylacetic acid (I) is chlorinated by means of SOCl2 in refluxing benzene. The resultant acid chloride (II) is then reacted with butylamine (III) to produce the target amide
| 【1】 Chan, H.C.; et al.; 4-Fluoro-N-butylphenylacetamide: A synthetic phenylacetate derivative that upregulates Bcl-X-S, activates caspase cascade and induces apoptosis in human squamous lung cancer CH27 cells. Cancer Lett 2002, 186, 2, 211. |