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【结 构 式】 
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【分子编号】20597 【品名】1-ethynylbenzene 【CA登记号】536-74-3 |
【 分 子 式 】C8H6 【 分 子 量 】102.13564 【元素组成】C 94.08% H 5.92% |
合成路线1
该中间体在本合成路线中的序号：(X)The condensation of 3-methoxybenzaldehyde (I) with acetone (II) by means of NaOH gives 1-(3-methoxyphenyl)-1-buten-3-one (III), which is hydrogenated with H2 over Pd/C in methanol yielding 1-(3-methoxyphenyl)-3-butanone (IV). The iodination of (IV) with I2-silver acetate in acetic acid affords 1-(2-iodo-5-methoxyphenyl)-3-butanone (V), which is reductocondensed with methylamine and sodium cyanoborohydride in methanol giving 2-iodo-5-methoxy-N,alpha-dimethylphenylpropanamine (VI). The acylation of (VI) with 3,4-dimethoxyphenylacetyl chloride (VII) by means of triethylamine in dichloromethane yields the corresponding acetamide (VIII), which is reduced with borane-THF complex affording the corresponding tertiary amine (IX), which is finally condensed with phenylacetylene (X) by means of butyllithium in THF.
| 【1】 Carson, J.R. (McNeilab, Inc.); Aralkyl(arylethynyl)aralkyl amines for use as vasodilators and antihypertensives. EP 0146271; ES 8604488; US 4661635 . |
| 【2】 Prous, J.; Castaner, J.; McN-5691. Drugs Fut 1989, 14, 4, 322. |
| 【3】 Carson, J.R.; Almond, H.R.; Brannan, M.D.; et al.; 2-Ethynylbenzenealkanamines. A new class of calcium entry blockers. J Med Chem 1988, 31, 3, 630-6. |
| 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) | 20589 | 3-methoxybenzaldehyde; m-Anisaldehyde | 591-31-1 | C8H8O2 | 详情 | 详情 |
| (II) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (III) | 20590 | (E)-4-(3-methoxyphenyl)-3-buten-2-one | C11H12O2 | 详情 | 详情 | |
| (IV) | 20591 | 4-(3-methoxyphenyl)-2-butanone | C11H14O2 | 详情 | 详情 | |
| (V) | 20592 | 4-(2-iodo-5-methoxyphenyl)-2-butanone | C11H13IO2 | 详情 | 详情 | |
| (VI) | 20593 | N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylamine; 4-(2-iodo-5-methoxyphenyl)-N-methyl-2-butanamine | C12H18INO | 详情 | 详情 | |
| (VII) | 20594 | 2-(3,4-dimethoxyphenyl)acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
| (VIII) | 20595 | 2-(3,4-dimethoxyphenyl)-N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylacetamide | C22H28INO4 | 详情 | 详情 | |
| (IX) | 20596 | N-(3,4-dimethoxyphenethyl)-N-[3-(2-iodo-5-methoxyphenyl)-1-methylpropyl]-N-methylamine; N-(3,4-dimethoxyphenethyl)-4-(2-iodo-5-methoxyphenyl)-N-methyl-2-butanamine | C22H30INO3 | 详情 | 详情 | |
| (X) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of p-cresol (I) with phenylacetylene (II) by means of acid activated alumina in refluxing dichlorobenzene gives 4-methyl-2-(1-phenylvinyl)phenol (III), which is hydroformylated with CO, H2 and a Rh catalyst in hot toluene to yield 3-(2-hydroxy-5-methylphenyl)-3-phenylpropionaldehyde (IV), mostly in the hemiacetalic form (V). The reaction of (V) with diisopropylamine (VI) in hot toluene catalyzed by molecular sieves gives the enamine (VII), which is finally hydrogenated with H2 over PtO2 in refluxing toluene to afford the target racemic tolterodine. Alternatively, the reductocondensation of hemiacetal (V) with diisopropylamine (VI) by means of H2 over Pd/C in hot methanol provides directly the target racemic tolterodine.
| 【1】 Paganelli, S.; Piccolo, O.; Botteghi, C.; Marchetti, M.; Corrias, T.; A new efficient route to tolterodine. Org Process Res Dev 2002, 6, 7, 379. |
| 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) | 37678 | p-cresol | 106-44-5 | C7H8O | 详情 | 详情 |
| (II) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
| (III) | 56853 | 4-methyl-2-(1-phenylvinyl)phenol | C15H14O | 详情 | 详情 | |
| (IV) | 56854 | 3-(2-hydroxy-5-methylphenyl)-3-phenylpropanal | C16H16O2 | 详情 | 详情 | |
| (V) | 37679 | 6-methyl-4-phenyl-2-chromanol | C16H16O2 | 详情 | 详情 | |
| (VI) | 13565 | N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine | 108-18-9 | C6H15N | 详情 | 详情 |
| (VII) | 56855 | 2-[(E)-3-(diisopropylamino)-1-phenyl-2-propenyl]-4-methylphenol | C22H29NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The alkylation of phenylacetylene (I) with AlMe3 and ZnCl2CP2 gives the alpha-methylstyrene (II), which is treated with paraformaldehyde and BuLi to yield 3-phenyl-2-buten-1-ol (III). The reaction of (III) with NCS and DMS affords the butenyl chloride (IV), which is treated with trichlorosilane, TEA and CuCl to provide the allylic trichlorosilane (V). The condensation of (V) with benzaldehyde (VI) by means of the chiral catalyst (VII) and tetrabutylammonium iodide in dichloromethane gives the chiral diphenylcarbinol (VIII), which is submitted to hydroboration by means of 9-BBN and NaBO3 to yield the diol (IX). The selective, two step reduction of one phenyl group of (IX) with H2 over Rh/alumina and H2 over Pt/C affords the chiral cyclohexyl-butanediol derivative (X), which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to provide the keto-aldehyde (XI). Finally, this compound is reductocondensed with 1-(2-methoxyphenyl)piperazine (XII) by means of NaBH(OAc)3 in 1,2-dichloroethane to give the target disubstituted piperazine.
| 【1】 Denmark, S.E.; Fu, J.; Asymmetric construction of quaternary centers by enantioselective allylation: Application to the synthesis of the serotonin antagonist lY426965. Org Lett 2002, 4, 11, 1951. |
| 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) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
| (II) | 28450 | 1-isopropenylbenzene | 98-83-9 | C9H10 | 详情 | 详情 |
| (III) | 57208 | (E)-3-phenyl-2-buten-1-ol | C10H12O | 详情 | 详情 | |
| (IV) | 57209 | 1-[(E)-3-chloro-1-methyl-1-propenyl]benzene | C10H11Cl | 详情 | 详情 | |
| (V) | 57210 | trichloro[(E)-3-phenyl-2-butenyl]silane | C10H11Cl3Si | 详情 | 详情 | |
| (VI) | 57211 | (9aS,9bS)-5-[{5-[[(9aS,9bS)-5-oxooctahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-yl](methyl)amino]pentyl}(methyl)amino]octahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-one | C23H44N6O2P2 | 详情 | 详情 | |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 57212 | (1S,2S)-2-methyl-1,2-diphenyl-3-buten-1-ol | C17H18O | 详情 | 详情 | |
| (IX) | 57213 | (1S,2S)-2-methyl-1,2-diphenyl-1,4-butanediol | C17H20O2 | 详情 | 详情 | |
| (X) | 57214 | (1S,2S)-1-cyclohexyl-2-methyl-2-phenyl-1,4-butanediol | C17H26O2 | 详情 | 详情 | |
| (XI) | 57215 | (3S)-4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal | C17H22O2 | 详情 | 详情 | |
| (XII) | 11882 | 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine | 35386-24-4 | C11H16N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation between 2-iodo-5-fluoroaniline (I) and phenylacetylene (II) under catalysis with Pd(PPh3)4, CuI and diethylamine, followed by cyclization catalyzed by CuI and CaCO3 in DMF, affords phenylindole (III), which is then coupled with 4-piperidone (IV) in H3PO4/HOAc to provide tetrahydropyridine derivative (V). Protection of (V) as its benzyloxycarbonyl derivative (VII) by reaction with acid chloride (VI), followed by hydroboration with bis-isopinocampheylborane ((-)-Ipc2BH) and H2O2 in NaOH, provides the secondary alcohol (VIII). Isolation of enantiomer (IX) is then performed by reaction of (VIII) with the acid chloride derived from (1R)-(+)-camphanic acid, separation of diastereoisomers by chromatography and hydrolysis with K2CO3 in MeOH. Treatment of (IX) with diethylaminosulfur trifluoride (DAST) in EtOAc induces a regiospecific and enantioselective rearrangement affording 3-(3-indolyl)-4-fluoropiperidine (X), which is finally converted into the desired compound by deprotection with formic acid and Pd/C.
| 【1】 Rowley, M.; et al.; 3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT2A receptor antagonists. J Med Chem 2001, 44, 10, 1603. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 50178 | 7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride | C9H11ClO3 | 详情 | 详情 | ||
| (I) | 50173 | 5-fluoro-2-iodoaniline; 5-fluoro-2-iodophenylamine | C6H5FIN | 详情 | 详情 | |
| (II) | 20597 | 1-ethynylbenzene | 536-74-3 | C8H6 | 详情 | 详情 |
| (III) | 50174 | 6-fluoro-2-phenyl-1H-indole | C14H10FN | 详情 | 详情 | |
| (IV) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 详情 | 详情 |
| (V) | 50175 | 6-fluoro-2-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole | C19H17FN2 | 详情 | 详情 | |
| (VI) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 50176 | benzyl 4-[2-(1,2,3,5-cyclohexatetraen-1-yl)-6-fluoro-1H-indol-3-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate | C27H21FN2O2 | 详情 | 详情 | |
| (VIII) | 50177 | benzyl 4-(6-fluoro-2-phenyl-1H-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate | C27H25FN2O3 | 详情 | 详情 | |
| (IX) | 50179 | benzyl (3S,4S)-4-(6-fluoro-2-phenyl-1H-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate | C27H25FN2O3 | 详情 | 详情 | |
| (X) | 50180 | benzyl (3R,4R)-4-fluoro-3-(6-fluoro-2-phenyl-1H-indol-3-yl)-1-piperidinecarboxylate | C27H24F2N2O2 | 详情 | 详情 |