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【结 构 式】 
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【分子编号】43386 【品名】(3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide 【CA登记号】 |
【 分 子 式 】C15H23NS 【 分 子 量 】249.42036 【元素组成】C 72.23% H 9.29% N 5.62% S 12.86% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reaction of 3-(1-propylpiperidin-3(S)-yl)phenol (I) with trifluoromethanesulfonic anhydride gives the triflate (II), which is treated with Pd(OAc)4, CO and MeOH, yielding 3-(1-propylpiperidin-3(S)-yl)benzoic acid methyl ester (III). The reaction of (III) with sodium azide and H2SO4 affords the aniline (IV), which by reaction with NaNO2, HBr and CuBr provides 3(S)-(3-bromophenyl)-1-propylpiperidine (V). The reaction of (V) with dimethyl disulfide and n-BuLi gives the thioether (VI), which is oxidized with MCPBA to afford the target sulfone, which is easily separated from the N-oxide (VII) also formed in the oxidation process. The N-oxide (VII) can be reduced to the target compound by means of TiCl4 and NaI in acetonitrile.
| 【1】 Sonesson, C.; et al.; Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: Synthesis and structure-activity relationships. J Med Chem 1994, 37, 17, 2735. |
| 【2】 Svensson, K.A.I.; Wikström, H.V.; Carlsson, P.A.E.; Boije, A.M.P.; Waters, R.N.; Sonesson, C.A.; Stjerulof, N.P.; Andersson, B.R. (Pharmacia Corp.); New centrally acting substd. phenylazacycloalkanes. EP 0641320; JP 1994509561; US 5462947; WO 9218475 . |
| 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) | 43381 | 3-[(3S)-1-propylpiperidinyl]phenol | C14H21NO | 详情 | 详情 | |
| (II) | 43382 | 3-[(3S)-1-propylpiperidinyl]phenyl trifluoromethanesulfonate | C15H20F3NO3S | 详情 | 详情 | |
| (III) | 43383 | methyl 3-[(3S)-1-propylpiperidinyl]benzoate | C16H23NO2 | 详情 | 详情 | |
| (IV) | 43384 | 3-[(3S)-1-propylpiperidinyl]phenylamine; 3-[(3S)-1-propylpiperidinyl]aniline | C14H22N2 | 详情 | 详情 | |
| (V) | 43385 | (3S)-3-(3-bromophenyl)-1-propylpiperidine | C14H20BrN | 详情 | 详情 | |
| (VI) | 43386 | (3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide | C15H23NS | 详情 | 详情 | |
| (VII) | 43387 | (3S)-3-[3-(methylsulfonyl)phenyl]-1-propyl-1-piperidiniumolate | C15H23NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The reaction of 3-(1-propylpiperidin-3(S)-yl)phenol (I) with trifluoromethanesulfonic anhydride gives the triflate (II), which is treated with triisopropylsilylthiol sodium salt and Pd(PPh3)4 to yield the sill sulfanyl compound (III). The desilylation of (III) with HCl in methanol affords the thiophenol (IV), which is methylated with 13C- and 2H-labeled methyl iodide and TEA in dichloromethane, providing the methylsulfanyl derivative (V). Finally, this compound is oxidized to the target sulfone with MCPBA and trifluoroacetic acid.
| 【1】 Chaudhary, A.G.; McGrath, J.P.; Improved synthesis of stable isotope labeled and carbon-14 labeled (S)-(-)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride; (-)-OSU-6162. J Label Compd Radiopharm 2000, 43, 7, 683. |
| 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) | 43381 | 3-[(3S)-1-propylpiperidinyl]phenol | C14H21NO | 详情 | 详情 | |
| (II) | 43382 | 3-[(3S)-1-propylpiperidinyl]phenyl trifluoromethanesulfonate | C15H20F3NO3S | 详情 | 详情 | |
| (III) | 43392 | 3-[(3S)-1-propylpiperidinyl]phenyl triisopropylsilyl sulfide; (3S)-1-propyl-3-[3-[(triisopropylsilyl)sulfanyl]phenyl]piperidine | C23H41NSSi | 详情 | 详情 | |
| (IV) | 43393 | 3-[(3S)-1-propylpiperidinyl]phenylhydrosulfide; 3-[(3S)-1-propylpiperidinyl]benzenethiol | C14H21NS | 详情 | 详情 | |
| (V) | 43386 | (3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide | C15H23NS | 详情 | 详情 | |
| (V) | 45317 | methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide; (3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine | C15H23NS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The reaction of 3-(1-propylpiperidin-3(S)-yl)phenol (I) with trifluoromethanesulfonic anhydride gives the triflate (II), which is treated with triisopropylsilylthiol sodium salt and Pd(PPh3)4 to yield the sill sulfanyl compound (III). The desilylation of (III) with HCl in methanol affords the thiophenol (IV), which is methylated with 14C-labeled methyl iodide and TEA in dichloromethane, providing the methylsulfanyl derivative (V). Finally, this compound is oxidized to the target sulfone with MCPBA and trifluoroacetic acid.
| 【1】 Chaudhary, A.G.; McGrath, J.P.; Improved synthesis of stable isotope labeled and carbon-14 labeled (S)-(-)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride; (-)-OSU-6162. J Label Compd Radiopharm 2000, 43, 7, 683. |
| 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) | 43381 | 3-[(3S)-1-propylpiperidinyl]phenol | C14H21NO | 详情 | 详情 | |
| (II) | 43382 | 3-[(3S)-1-propylpiperidinyl]phenyl trifluoromethanesulfonate | C15H20F3NO3S | 详情 | 详情 | |
| (III) | 43392 | 3-[(3S)-1-propylpiperidinyl]phenyl triisopropylsilyl sulfide; (3S)-1-propyl-3-[3-[(triisopropylsilyl)sulfanyl]phenyl]piperidine | C23H41NSSi | 详情 | 详情 | |
| (IV) | 43393 | 3-[(3S)-1-propylpiperidinyl]phenylhydrosulfide; 3-[(3S)-1-propylpiperidinyl]benzenethiol | C14H21NS | 详情 | 详情 | |
| (V) | 43386 | (3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide | C15H23NS | 详情 | 详情 | |
| (V) | 45318 | (3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide | C15H23NS | 详情 | 详情 | |
| (V) | 53280 | (3S)-3-[3-(methylsulfanyl)phenyl]-1-propylpiperidine; methyl 3-[(3S)-1-propylpiperidinyl]phenyl sulfide | n/a | C15H23NS | 详情 | 详情 |