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【结 构 式】 
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【分子编号】50647 【品名】benzyl (3R)-3-methyl-1-piperazinecarboxylate 【CA登记号】 |
【 分 子 式 】C13H18N2O2 【 分 子 量 】234.2982 【元素组成】C 66.64% H 7.74% N 11.96% O 13.66% |
合成路线1
该中间体在本合成路线中的序号：(XII)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：(IV)The reaction of the chiral benzyl alcohol (I) with 4-chlorobenzenesulfonyl chloride (II) and DABCO in toluene gives the sulfonate (III), which is condensed with the monoprotected piperazine (IV) by means of K2CO3 in hot toluene/acetonitrile to yield the adduct (V). The deprotection of (V) by means of hot aqueous HCl affords the piperazine derivative (VI), which is condensed with the acyl piperidine (VII) --obtained by condensation of 4,6-dimethylpyrimidine-5-carboxylic acid (VIII) with 4-piperidone (IX) --by means of acetone cyanohydrin or NaCN/AcOH to provide the cyano adduct (X). Finally, this compound is treated with AlMe3 and Me-MgCl in THF/toluene to yield the target compound.
| 【1】 Gala, D.; Leong, W.; Jones, A.D.; Shi, X.; Chen, M.; D'sa, B.A.; Zhu, M.; Xiao, T.; Tang, S.; Goodman, A.J.; Nielsen, C.M.; Lee, G.M.; Gamboa, J.A. (Schering Corp.); Synthesis of piperidine and piperazine cpds. as CCR5 antagonists. WO 0384950 . |
| 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) | 64951 | (1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]-1-ethanol | C10H11F3O2 | 详情 | 详情 | |
| (II) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (III) | 64952 | (1S)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl 4-chlorobenzenesulfonate | C16H14ClF3O4S | 详情 | 详情 | |
| (IV) | 50647 | benzyl (3R)-3-methyl-1-piperazinecarboxylate | C13H18N2O2 | 详情 | 详情 | |
| (V) | 64953 | benzyl (3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methyl-1-piperazinecarboxylate | C23H27F3N2O3 | 详情 | 详情 | |
| (VI) | 64946 | 2-methyl-1-{2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}piperazine; methyl 2-(2-methyl-1-piperazinyl)-2-[4-(trifluoromethyl)phenyl]ethyl ether | C15H21F3N2O | 详情 | 详情 | |
| (VII) | 64954 | 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-piperidinone | C12H15N3O2 | 详情 | 详情 | |
| (VIII) | 64955 | 4,6-dimethyl-5-pyrimidinecarboxylic acid | C7H8N2O2 | 详情 | 详情 | |
| (IX) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (X) | 64956 | 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-((3S)-4-{(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazinyl)-4-piperidinecarbonitrile | C28H35F3N6O2 | 详情 | 详情 |