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【结 构 式】 
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【分子编号】13565 【品名】N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine 【CA登记号】108-18-9 |
【 分 子 式 】C6H15N 【 分 子 量 】101.19184 【元素组成】C 71.22% H 14.94% N 13.84% |
合成路线1
该中间体在本合成路线中的序号：(V)The reaction of 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (I) with methyl iodide and K2CO3 in refluxing acetone/methanol or dimethyl sulfate and NaOH gives 3-(2-methoxy-5-phenylphenyl)-3-phenylpropionic acid methyl ester (II), which is reduced with LiAlH4 in ether or NaBH4 and AlCl3 to the corresponding propanol (III). The reduction of (III) with tosyl chloride and pyridine yields the expected tosylate (IV), which by condensation with diisopropylamine (V) in hot acetonitrile is converted into the tertiary amine (VI). Finally, this compound is treated with BBr3 in dichloromethane or HBr to afford the expected amine (VII) as a racemic mixture, which is resolved with L-(+)-tartaric acid.
| 【1】 Graul, A.; Martel, A.M.; Castaner, J.; Tolterodine. Drugs Fut 1997, 22, 7, 733. |
| 【2】 Jonsson, N.A.; Sparf, B.A.; Mikiver, L.; Moses, P.; Nilvebrant, L.; Glas, G. (Pharmacia Corp.); New amines, their use and preparation. EP 0325571; JP 1991503163; US 5382600; WO 8906644 . |
| 【3】 Kumar, Y.; Prasad, M.; Neela, P.K.; Misra, S. (Ranbaxy Laboratories Ltd.); Process for the preparation of tolterodine. WO 0314060 . |
| 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) | 13561 | 6-Methyl-4-phenyl-2-chromanone | C16H14O2 | 详情 | 详情 | |
| (II) | 13562 | methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropanoate | C18H20O3 | 详情 | 详情 | |
| (III) | 13563 | 3-(2-Methoxy-5-methylphenyl)-3-phenyl-1-propanol | C17H20O2 | 详情 | 详情 | |
| (IV) | 13564 | 3-(2-methoxy-5-methylphenyl)-3-phenylpropyl 4-methylbenzenesulfonate | C24H26O4S | 详情 | 详情 | |
| (V) | 13565 | N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine | 108-18-9 | C6H15N | 详情 | 详情 |
| (VI) | 13566 | N,N-Diisopropyl-N-[3-(2-methoxy-5-methylphenyl)-3-phenylpropyl]amine; N,N-Diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenyl-1-propanamine | C23H33NO | 详情 | 详情 | |
| (VII) | 13567 | 2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol | C22H31NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)A new process for the preparation of tolterodine has been described: The cyclization of trans-cinnamic acid (I) with p-cresol (II) by means of hot sulfuric acid gives 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (III), which is reduced with DIBAL in toluene, yielding 6-methyl-4-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol (IV). The reductocondensation of (IV) with diisopropylamine (V) by means of H2 over Pd/C in methanol affords racemic tolterodine (VI), which is finally submitted to optical resolution with L-tartaric acid in dichloromethane/water.
| 【1】 Gage, J.R.; Cabaj, J.E. (Pharmacia Corp.); Process to prepare tolterodine. US 5992914; WO 9829402 . |
| 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) | 37680 | (2E)-3-phenyl-2-propenoic acid; trans-Cinnamic acid; trans-3-Phenylacrylic acid | 140-10-3 | C9H8O2 | 详情 | 详情 |
| (II) | 37678 | p-cresol | 106-44-5 | C7H8O | 详情 | 详情 |
| (III) | 13561 | 6-Methyl-4-phenyl-2-chromanone | C16H14O2 | 详情 | 详情 | |
| (IV) | 37679 | 6-methyl-4-phenyl-2-chromanol | C16H16O2 | 详情 | 详情 | |
| (V) | 13565 | N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine | 108-18-9 | C6H15N | 详情 | 详情 |
| (VI) | 13567 | 2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol | C22H31NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The condensation of 2'-bromo-4'-methylacetophenone (I) with benzaldehyde (II) by means of NaOMe in methanol gives the propenone (III), which is cyclized by means of PdCl2, PPh3 and K2CO3 in DMF, yielding 5-methyl-3-phenyl-1-indenone (IV). The enantioselective reduction of (IV) by means of borane/Me2S complex and (R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole [(R)-MeCBS] as chiral catalyst in THF affords 5-methyl-3(S)-phenylindan-1-ol (V), which is oxidized with 1,4-diazabicyclo[2,2,2]octane (DABCO) in refluxing THF/TEA to provide the corresponding indanone (VI). The oxidation of (VI) with MCPBA in dichloromethane gives 6-methyl-4(S)-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (VII), which is reduced with DIBAL in toluene to yield 6-methyl-4(S)-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol (VIII). Finally, this compound is reductocondensed with diisopropylamine (IX) by means of H2 over Pd/C in methanol to afford the target compound.
| 【1】 Andersson, P.G.; Hedberg, C. (Pharmacia & Upjohn AB); Process of preparing tolterodine and analogues there of as well as intermediates prepared in the process. WO 0149649 . |
| 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) | 55510 | 1-(2-bromo-4-methylphenyl)-1-ethanone | C9H9BrO | 详情 | 详情 | |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 55511 | (E)-1-(2-bromo-4-methylphenyl)-3-phenyl-2-propen-1-one | C16H13BrO | 详情 | 详情 | |
| (IV) | 55512 | 5-methyl-3-phenyl-1H-inden-1-one | C16H12O | 详情 | 详情 | |
| (V) | 55513 | (3R)-5-methyl-3-phenyl-2,3-dihydro-1H-inden-1-ol | C16H16O | 详情 | 详情 | |
| (VI) | 55514 | (3R)-5-methyl-3-phenyl-2,3-dihydro-1H-inden-1-one | C16H14O | 详情 | 详情 | |
| (VII) | 55515 | (4R)-6-methyl-4-phenyl-3,4-dihydro-2H-chromen-2-one | C16H14O2 | 详情 | 详情 | |
| (VIII) | 55516 | (4R)-6-methyl-4-phenyl-3,4-dihydro-2H-chromen-2-ol | C16H16O2 | 详情 | 详情 | |
| (IX) | 13565 | N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine | 108-18-9 | C6H15N | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)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5
该中间体在本合成路线中的序号：(VI)The reaction of terephthalic acid monomethyl ester (I) with SOCl2 in dichloromethane gives the acyl chloride (II), which is condensed with 3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidin-4-amine (III) by means of TEA in dichloromethane, yielding the corresponding amide (IV). The cyclization of (IV) by means of POCl3 in refluxing acetonitrile affords the benzo-naphthyridine (V), which is treated with diisopropylamine in methanol to provide the target diisopropyl carboxamide.
| 【1】 Gutterer, B.; Amschler, H.; Ulrich, W.-R.; Martin, T.; Bär, T.; Hatzelmann, A.; Sanders, K.; Beume, R.; Boss, H.; Häfner, D.; Kley, H.-P.; Goebel, K.-J. (Altana Pharma Deutschland GmbH ); Benzonaphthyridines as bronchial therapeutics. EP 0937074; JP 2001503442; US 6008215; WO 9821208 . |
| 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) | 43361 | 4-(methoxycarbonyl)benzoic acid | 1679-64-7 | C9H8O4 | 详情 | 详情 |
| (II) | 25029 | p-Phthalic acid monomethyl ester chloride; Terephthalic acid monomethyl ester chloride; Methyl 4-chlorocarbonylbenzoate | 7377-26-6 | C9H7ClO3 | 详情 | 详情 |
| (III) | 53959 | 3-(3-ethoxy-4-methoxyphenyl)-1-methyl-4-piperidinamine; 3-(3-ethoxy-4-methoxyphenyl)-1-methyl-4-piperidinylamine | n/a | C15H24N2O2 | 详情 | 详情 |
| (IV) | 53960 | methyl 4-({[3-(3-ethoxy-4-methoxyphenyl)-1-methyl-4-piperidinyl]amino}carbonyl)benzoate | n/a | C24H30N2O5 | 详情 | 详情 |
| (V) | 53961 | methyl 4-[(4aS,10bR)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridin-6-yl]benzoate | n/a | C24H28N2O4 | 详情 | 详情 |
| (VI) | 13565 | N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine | 108-18-9 | C6H15N | 详情 | 详情 |