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【结 构 式】 
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【分子编号】28620 【品名】1,3-benzodioxole-5-thiol 【CA登记号】 |
【 分 子 式 】C7H6O2S 【 分 子 量 】154.18944 【元素组成】C 54.53% H 3.92% O 20.75% S 20.8% |
合成路线1
该中间体在本合成路线中的序号：(XI)The esterification of 3,4-dimethoxy-2-nitrobenzoic acid (I) with methyl iodide and cesium carbonate gives the corresponding methyl ester (II), which is reduced with H2 over Pd/C yielding the expected 2-amino compound (III). The reaction of (III) with NaNO2 and SO2 affords the disulfide (IV), which is cyclized with methyl glycinate (V) by means of KNO3 and SO2Cl2 giving the benzoisothiazolone derivative (VI). The rearrangement of (VI) by means of sodium methoxide yields the 1,2-benzothiazine derivative (VII), which is condensed with 3,4-methylenedioxybenzyl chloride (VIII) by means of NaH in DMF affording the N-substituted benzothiazine (IX). The reaction of (IX) with triflic anhydride gives the triflate ester (X), which is condensed with 3,4-methylenedioxythiophenol (XI) by means of NaH in DMF and hydrolyzed with LiOH in THF to provide the target compound.
| 【1】 Berryman, K.A.; Edmunds, J.J.; Bunker, A.M.; Haleen, S.; Bryant, J.; Welch, K.M.; Doherty, A.M.; Endothelin receptor antagonists: Synthesis and structure-activity relationships of substituted benzothiazine-1,1-dioxides. Bioorg Med Chem 1998, 6, 9, 1447. |
| 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) | 28611 | 3,4-dimethoxy-2-nitrobenzoic acid | C9H9NO6 | 详情 | 详情 | |
| (II) | 28612 | methyl 3,4-dimethoxy-2-nitrobenzoate | C10H11NO6 | 详情 | 详情 | |
| (III) | 28613 | methyl 2-amino-3,4-dimethoxybenzoate | C10H13NO4 | 详情 | 详情 | |
| (IV) | 28614 | methyl 2-[[2,3-dimethoxy-6-(methoxycarbonyl)phenyl]disulfanyl]-3,4-dimethoxybenzoate | C20H22O8S2 | 详情 | 详情 | |
| (V) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VI) | 28615 | methyl 2-(6,7-dimethoxy-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C12H13NO7S | 详情 | 详情 | |
| (VII) | 28616 | methyl 4-hydroxy-7,8-dimethoxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C12H13NO7S | 详情 | 详情 | |
| (VIII) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (IX) | 28618 | methyl 2-(1,3-benzodioxol-5-ylmethyl)-4-hydroxy-7,8-dimethoxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C20H19NO9S | 详情 | 详情 | |
| (X) | 28619 | methyl 2-(1,3-benzodioxol-5-ylmethyl)-7,8-dimethoxy-1,1-dioxo-4-[[(trifluoromethyl)sulfonyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C21H18F3NO11S2 | 详情 | 详情 | |
| (XI) | 28620 | 1,3-benzodioxole-5-thiol | C7H6O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)N-protection of the NH group of (I) with Boc2O and NaOH in Et2O yields derivative (II), which is then condensed with compound (III) by means of NaH in DMF to provide (IV). N-deprotection of (IV) by treatment with TFA in CH2Cl2 followed by reductocondensation with N-Boc-4-piperidone (V) in CH2Cl2 in the presence of Na(OAc)3BH affords compound (VI), which is oxidized with NaBO3.4H2O to provide (VII). Boc removal of (VII) by treatment with TFA in CH2Cl2, followed by reaction of the resulting secondary amine with sulfonyl chloride (VIII) in CH2Cl2 in the presence of Et3N, affords propylsulfonamide derivative (IX). Finally, treatment of (IX) with ethyleneglycol (X) in toluene in the presence of HC(OEt)3 and p-TsOH furnishes the target compound.
| 【1】 Boyle, C.D.; Chackalamannil, S.; Chen, L.-Y.; et al.; Benzylidine ketal derivatives as M2 muscarinic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 24, 2727. |
| 【2】 Chackalamannil, S.; Chen, L.-Y.; Boyle, C.D.; et al.; Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 114. |
| 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) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (II) | 45867 | tert-butyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate | C17H22FNO3 | 详情 | 详情 | |
| (III) | 28620 | 1,3-benzodioxole-5-thiol | C7H6O2S | 详情 | 详情 | |
| (IV) | 45868 | tert-butyl 4-[4-(1,3-benzodioxol-5-ylsulfanyl)benzoyl]-1-piperidinecarboxylate | C24H27NO5S | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 45869 | C29H36N2O5S | 详情 | 详情 | ||
| (VII) | 45870 | C29H36N2O7S | 详情 | 详情 | ||
| (VIII) | 45871 | 1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride; | 10147-36-1 | C3H7ClO2S | 详情 | 详情 |
| (IX) | 45872 | C27H34N2O7S2 | 详情 | 详情 | ||
| (X) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)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 |