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【结 构 式】 
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【分子编号】50649 【品名】(2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone 【CA登记号】 |
【 分 子 式 】C20H24N2O4S 【 分 子 量 】388.48764 【元素组成】C 61.83% H 6.23% N 7.21% O 16.47% S 8.25% |
合成路线1
该中间体在本合成路线中的序号：(XIV)Lithiation of 5-bromo-1,3-benzodioxole (I), followed by reaction with elemental sulfur gave disulfide (II), which was reduced to thiol (III) by using LiAlH4. In an alternative procedure, thiol (III) was prepared by chlorosulfonation of benzodioxole (IV) and then reduction of the resulting sulfonyl chloride (V) with LiAlH4. Condensation of thiol (III) with p-fluoroacetophenone (VI) provided the diaryl sulfide (VII). Asymmetric reduction of the keto group of (VII) employing borane-dimethyl sulfide complex in the presence of the chiral oxazaborole auxiliary (VIII) yielded the (R)-alcohol (IX), which was converted to mesylate (XI) by oxidation with MCPBA to sulfone (X), a treatment with methanesulfonyl chloride and triethylamine. Alkylation of benzyl (R)-3-methylpiperazine-1-carboxylate (XII) with the chiral mesylate (XI) gave adduct (XIII). The benzyloxycarbonyl protecting group of (XIII) was then removed by acid hydrolysis, yielding piperazine (XIV).
| 【1】 Muscarinic antagonists. WO 9805292 . |
| 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) | 10124 | 5-Bromo-1,3-benzodioxole; 4-Bromo-1,2-(methylenedioxy)benzene | 2635-13-4 | C7H5BrO2 | 详情 | 详情 |
| (II) | 50640 | 5-(1,3-benzodioxol-5-yldisulfanyl)-1,3-benzodioxole; di(1,3-benzodioxol-5-yl) disulfide | C14H10O4S2 | 详情 | 详情 | |
| (III) | 28620 | 1,3-benzodioxole-5-thiol | C7H6O2S | 详情 | 详情 | |
| (IV) | 50641 | 1,3-Dioxaindane; 1,3-Benzodioxole; methylenedioxybenzene; 1,2-methylenedioxybenzene; catechol methylene ether | 274-09-9 | C7H6O2 | 详情 | 详情 |
| (V) | 50642 | 1,3-benzodioxole-5-sulfonyl chloride | C7H5ClO4S | 详情 | 详情 | |
| (VI) | 37684 | 1-(4-fluorophenyl)-1-ethanone | 403-42-9 | C8H7FO | 详情 | 详情 |
| (VII) | 50643 | 1-[4-(1,3-benzodioxol-5-ylsulfanyl)phenyl]-1-ethanone | C15H12O3S | 详情 | 详情 | |
| (VIII) | 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 |
| (IX) | 50644 | (1R)-1-[4-(1,3-benzodioxol-5-ylsulfanyl)phenyl]-1-ethanol | C15H14O3S | 详情 | 详情 | |
| (X) | 50645 | (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanol | C15H14O5S | 详情 | 详情 | |
| (XI) | 50646 | (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl methanesulfonate | C16H16O7S2 | 详情 | 详情 | |
| (XII) | 50647 | benzyl (3R)-3-methyl-1-piperazinecarboxylate | C13H18N2O2 | 详情 | 详情 | |
| (XIII) | 50648 | benzyl (3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methyl-1-piperazinecarboxylate | C28H30N2O6S | 详情 | 详情 | |
| (XIV) | 50649 | (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone | C20H24N2O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Condensation of piperazine (XIV) with N-Boc-4-piperidinone (XV) in the presence of titanium isopropoxide as the dehydrating reagent, followed by addition of diethylaluminum cyanide to the intermediate iminium salt, provided the alpha-aminonitrile (XVI). The cyano group of (XVI) was subsequently displaced with methylmagnesium bromide, affording the methyl derivative (XVII). After acid cleavage of the Boc protecting group of (XVII), the resulting piperidine (XVIII) was finally acylated with propanesulfonyl chloride to furnish the corresponding sulfonamide.
| 【1】 Muscarinic antagonists. WO 9805292 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 50649 | (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone | C20H24N2O4S | 详情 | 详情 | |
| (XV) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (XVI) | 50650 | tert-butyl 4-((3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methylpiperazinyl)-4-cyano-1-piperidinecarboxylate | C31H40N4O6S | 详情 | 详情 | |
| (XVII) | 50651 | tert-butyl 4-((3R)-4-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-3-methylpiperazinyl)-4-methyl-1-piperidinecarboxylate | C31H43N3O6S | 详情 | 详情 | |
| (XVIII) | 50652 | (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methyl-4-(4-methyl-4-piperidinyl)piperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methyl-4-(4-methyl-4-piperidinyl)piperazinyl]ethyl]phenyl sulfone | C26H35N3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The reaction of 4-fluoroacetophenone (I) with sodium hydrogensulfide in hot DMF gives 4-sulfanylacetophenone (II), which is condensed with 5-iodo-1,3-benzodioxole (III) by means of CuI and K2CO3 in hot DMF to yield the thioether (IV). The oxidation of (IV) with MCPBA in dichloroethane affords the sulfone (V), which is enantioselectively reduced by means of BH3/SMe2 and Corey's oxoborolidine catalyst in THF to provide the chiral (R)-alcohol (VI). The reaction of (VI) with Ms-Cl in dichloromethane gives the mesylate (VII), which is condensed with the monoprotected 2(R)-methylpiperazine (VIII) by means of tetramethylpiperidine (TMP) in refluxing acetonitrile to yield the expected benzylic (S)-methyl compound (IX). The elimination of the Boc protecting group of (IX) with refluxing 6N HCl affords the piperazine derivative (X), which is reductocondensed with 1-(Boc)piperidin-4-one (XI) by means of NaBH(OAc)3 to provide adduct (XII). Elimination of the Boc protecting group of (XII) as before gives the piperidine derivative (XIII), which is finally sulfonated with ethylsulfonyl chloride and TEA to provide the target ethylsufonyl piperidine.
| 【1】 Kozlowski, J.A.; Zhou, G.; Tagat, J.R.; et al.; Substituted 2-(R)-methyl piperazines as muscarinic M2 selective ligands. Bioorg Med Chem Lett 2002, 12, 5, 791. |
| 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) | 37684 | 1-(4-fluorophenyl)-1-ethanone | 403-42-9 | C8H7FO | 详情 | 详情 |
| (II) | 54059 | 1-(4-sulfanylphenyl)-1-ethanone | n/a | C8H8OS | 详情 | 详情 |
| (III) | 54060 | 1-Iodo-3,4-methylenedioxybenzene | 5876-51-7 | C7H5IO2 | 详情 | 详情 |
| (IV) | 54061 | 1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanone | n/a | C15H12O5S | 详情 | 详情 |
| (V) | 50643 | 1-[4-(1,3-benzodioxol-5-ylsulfanyl)phenyl]-1-ethanone | C15H12O3S | 详情 | 详情 | |
| (VI) | 50645 | (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]-1-ethanol | C15H14O5S | 详情 | 详情 | |
| (VII) | 50646 | (1R)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl methanesulfonate | C16H16O7S2 | 详情 | 详情 | |
| (VIII) | 51868 | tert-butyl (3S)-3-methyl-1-piperazinecarboxylate | C10H20N2O2 | 详情 | 详情 | |
| (IX) | 54062 | tert-butyl (3R)-4-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate | n/a | C25H32N2O6S | 详情 | 详情 |
| (X) | 50649 | (2R)-1-[(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl]-2-methylpiperazine; 1,3-benzodioxol-5-yl 4-[(1S)-1-[(2R)-2-methylpiperazinyl]ethyl]phenyl sulfone | C20H24N2O4S | 详情 | 详情 | |
| (XI) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (XII) | 54063 | tert-butyl 4-((3R)-4-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-3-methylpiperazinyl)-1-piperidinecarboxylate | n/a | C30H41N3O6S | 详情 | 详情 |
| (XIII) | 54064 | (2R)-1-{(1S)-1-[4-(1,3-benzodioxol-5-ylsulfonyl)phenyl]ethyl}-2-methyl-4-(4-piperidinyl)piperazine; 1,3-benzodioxol-5-yl 4-{(1S)-1-[(2R)-2-methyl-4-(4-piperidinyl)piperazinyl]ethyl}phenyl sulfone | n/a | C25H33N3O4S | 详情 | 详情 |
| (XIV) | 54065 | Ethanesulfonyl chloride; Ethylsulfonyl chloride | 594-44-5 | C2H5ClO2S | 详情 | 详情 |