【结 构 式】 |
【分子编号】13561 【品名】6-Methyl-4-phenyl-2-chromanone 【CA登记号】 |
【 分 子 式 】C16H14O2 【 分 子 量 】238.28596 【元素组成】C 80.65% H 5.92% O 13.43% |
合成路线1
该中间体在本合成路线中的序号:(I)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:(III)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 |