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【结 构 式】 
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【分子编号】17473 【品名】diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide 【CA登记号】882-33-7 |
【 分 子 式 】C12H10S2 【 分 子 量 】218.3434 【元素组成】C 66.01% H 4.62% S 29.37% |
合成路线1
该中间体在本合成路线中的序号：(LX)6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII), which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV). The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII), which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI). 7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX), which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Kamikubo, T.; Takano, S.; Sugihara, T.; Suzuki, M.; Ogasawara, K.; Enantioconvergent synthesis of a promising HMG-CoA reductase inhibitor NK-104 from both enantiomers of epichlorohydrin. Tetrahedron Asymmetry 1993, 4, 2, 201-4. |
| 【3】 Iwasaki, H.; Miyachi, N.; Yanagawa, Y.; Ohara, Y.; Hiyama, T.; A novel synthetic method of HMG-CoA reductase inhibitor NK-104 via a hydroboration-cross-coupling sequence. Tetrahedron Lett 1993, 34, 51, 8267-70. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 17435 | 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline | C18H13FIN | 详情 | 详情 | |
| (XXXVII) | 17451 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methyl phenyl sulfide; 2-cyclopropyl-4-(4-fluorophenyl)-3-[(phenylsulfanyl)methyl]quinoline | C25H20FNS | 详情 | 详情 | |
| (LI) | 11661 | 2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid | 118-92-3 | C7H7NO2 | 详情 | 详情 |
| (LII) | 17465 | 2-aminobenzoyl chloride | C7H6ClNO | 详情 | 详情 | |
| (LIII) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
| (LIV) | 17467 | (2-aminophenyl)(4-fluorophenyl)methanone | C13H10FNO | 详情 | 详情 | |
| (LV) | 15949 | 3-Cyclopropyl-3-oxo-propionic acid ethyl ester; ethyl 3-cyclopropyl-3-oxopropanoate | 24922-02-9 | C8H12O3 | 详情 | 详情 |
| (LVI) | 12435 | Acetylcyclopropane; 1-Cyclopropyl-1-ethanone; Cyclopropylmethylketone | 765-43-5 | C5H8O | 详情 | 详情 |
| (LVII) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (LVIII) | 17471 | ethyl 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxylate | C21H18FNO2 | 详情 | 详情 | |
| (LIX) | 17472 | [2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]methanol | C19H16FNO | 详情 | 详情 | |
| (LX) | 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：4-Hydroxypiperidine (I) was protected as the tert-butyl carbamate (II) upon treatment with (Boc)2O. Subsequent Mitsunobu coupling of (II) with diphenyl disulfide using tributylphosphine and diethyl azodicarboxylate afforded thioether (III). Acid deprotection of the Boc group of (III), followed by nitrosation of the resulting amine (IV) gave N-nitrosopiperidine (V). Further reduction of (V) with LiAlH4 yielded hydrazine (VI). Condensation of (VI) with dichloropurine derivative (VII) produced piperidinyladenosine (VIII). Debenzoylation of the tribenzoate ester (VIII) with methanolic ammonia gave (IX). Then, chlorination at position 5' with concomitant formation of the 2',3' cyclic sulfite (X) by reaction with thionyl chloride and pyridine was followed by sulfite hydrolysis with methanolic ammonia to yield the title compound.
| 【1】 Lau, J.; Judge, M.E.; Sheardown, M.J.; Petersen, H.; Shalmi, M.; Knutsen, L.J.S.; Hansen, A.J.; Thomsen, C.; Weis, J.U.; N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects. J Med Chem 1999, 42, 18, 3463. |
| 【2】 Lau, J.; Knutsen, L.J.S. (Novo Nordisk A/S); Chemical cpds., their preparation and use. EP 0719275; JP 1999511436; US 5589467; WO 9507921 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 | |
| (I) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (II) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (III) | 32561 | tert-butyl 4-(phenylsulfanyl)-1-piperidinecarboxylate | C16H23NO2S | 详情 | 详情 | |
| (IV) | 32562 | 4-(phenylsulfanyl)piperidine; phenyl 4-piperidinyl sulfide | C11H15NS | 详情 | 详情 | |
| (V) | 32563 | 1-nitroso-4-piperidinyl phenyl sulfide; 1-nitroso-4-(phenylsulfanyl)piperidine | C11H14N2OS | 详情 | 详情 | |
| (VI) | 32564 | 4-(phenylsulfanyl)-1-piperidinamine; 4-(phenylsulfanyl)-1-piperidinylamine | C11H16N2S | 详情 | 详情 | |
| (VII) | 32565 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate | C31H22Cl2N4O7 | 详情 | 详情 | |
| (VIII) | 32568 | [(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C42H37ClN6O7S | 详情 | 详情 | |
| (IX) | 32566 | (2R,3R,4S,5R)-2-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C21H25ClN6O4S | 详情 | 详情 | |
| (X) | 32567 | (3aR,4S,6R,6aR)-4-(chloromethyl)-6-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)tetrahydro-2lambda(4)-furo[3,4-d][1,3,2]dioxathiol-2-one | C21H22Cl2N6O4S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The (phenylsulfanyl)piperidine (III) was obtained by condensation of N-Boc-4-piperidinol (I) with diphenyl disulfide (II) in the presence of tributylphosphine. Subsequent oxidation of sulfide (III) to the corresponding sulfone (IV) was achieved using oxone® on wet alumina. Deprotection of the N-Boc-piperidine (IV) with HCl afforded piperidine (V), which was finally alkylated with 2-bromo-4'-fluoroacetophenone (VI) to furnish the title N-phenacyl piperidine.
| 【1】 Blurton, P.; Burkamp, F.; Fletcher, S.R.; et al.; 4-(Phenylsulfonyl)piperidines: Novel, selective, and biovailable 5-HT2A receptor antagonists. J Med Chem 2002, 45, 2, 492. |
| 【2】 Macleod, A.M.; Blurton, P.; Fletcher, S.R.; Van Niel, M.B.; Burkamp, F.; Cheng, S.K.-F. (Merck Sharp & Dohme Ltd.); Phenylsulphonyl derivs. as 5-HT receptor ligands. EP 1147083; WO 0043362 . |
| 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) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (II) | 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 |
| (III) | 32561 | tert-butyl 4-(phenylsulfanyl)-1-piperidinecarboxylate | C16H23NO2S | 详情 | 详情 | |
| (IV) | 56311 | tert-butyl 4-(phenylsulfonyl)-1-piperidinecarboxylate | C16H23NO4S | 详情 | 详情 | |
| (V) | 56312 | 4-(phenylsulfonyl)piperidine; phenyl 4-piperidinyl sulfone | C11H15NO2S | 详情 | 详情 | |
| (VI) | 27904 | 2-bromo-1-(4-fluorophenyl)-1-ethanone | 403-29-2 | C8H6BrFO | 详情 | 详情 |