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【结 构 式】 
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【分子编号】37680 【品名】(2E)-3-phenyl-2-propenoic acid; trans-Cinnamic acid; trans-3-Phenylacrylic acid 【CA登记号】140-10-3 |
【 分 子 式 】C9H8O2 【 分 子 量 】148.16132 【元素组成】C 72.96% H 5.44% O 21.6% |
合成路线1
该中间体在本合成路线中的序号：(I)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2
该中间体在本合成路线中的序号：(I)3-Phenylindan-1-one (III) is prepared by either condensation between cinnamic acid (I) and benzene in the presence of AlCl3 or by Friedel-Crafts cyclization of 3,3-diphenylpropionic acid (II) in hot polyphosphoric acid. Claisen condensation of indanone (III) with diethyl carbonate affords keto ester (IV), which is further converted to enamino ester (V) upon treatment with ammonium acetate in boiling EtOH. Clauson-Kaas condensation of aminoindene (V) with 2,5-dimethoxytetrahydrofuran (VI) provides a mixture of isomeric pyrrolyl indenes (VII) and (VIII). Subsequent reduction of this mixture with NaBH4/NiCl2 affords the epimeric mixture of indanes (IX). Alkaline hydrolysis of esters (IX) proceeds with epimerization at C-2 to furnish the trans-trans acid (X). After activation of acid (X) as the corresponding mixed anhydride with ethyl chloroformate, coupling with pyrrolidine yields the target amide.
| 【1】 Rault, S.; Jarry, C.; Bovy, P.R.; Sopkova, J.; Dallemagne, P.; Guillon, J.; Leger, J.-M.; Synthesis of a novel class of non-peptide NK-2 receptor ligand, derived from 1-phenyl-3-pyrrol-1-ylidan-2-carboxamides. Bioorg Med Chem 2002, 10, 4, 1043. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 57778 | ethyl (1S,2S,3S)-1-phenyl-3-(1H-pyrrol-1-yl)-2,3-dihydro-1H-indene-2-carboxylate | C22H21NO2 | 详情 | 详情 | |
| (IXb) | 57779 | ethyl (1S,2R,3S)-1-phenyl-3-(1H-pyrrol-1-yl)-2,3-dihydro-1H-indene-2-carboxylate | C22H21NO2 | 详情 | 详情 | |
| (I) | 37680 | (2E)-3-phenyl-2-propenoic acid; trans-Cinnamic acid; trans-3-Phenylacrylic acid | 140-10-3 | C9H8O2 | 详情 | 详情 |
| (II) | 57773 | 3-Phenyl-1-indanone | 16618-72-7 | C15H12O | 详情 | 详情 |
| (III) | 36717 | 3,3-diphenylpropionic acid | 606-83-7 | C15H14O2 | 详情 | 详情 |
| (IV) | 57774 | ethyl (2R,3S)-1-oxo-3-phenyl-2,3-dihydro-1H-indene-2-carboxylate | C18H16O3 | 详情 | 详情 | |
| (V) | 57775 | ethyl (1S)-3-amino-1-phenyl-1H-indene-2-carboxylate | C18H17NO2 | 详情 | 详情 | |
| (VI) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (VII) | 57776 | ethyl 1-phenyl-3-(1H-pyrrol-1-yl)-1H-indene-2-carboxylate | C22H19NO2 | 详情 | 详情 | |
| (VIII) | 57777 | ethyl 3-phenyl-1-(1H-pyrrol-1-yl)-1H-indene-2-carboxylate | C22H19NO2 | 详情 | 详情 | |
| (X) | 57780 | (1S,2R,3S)-1-phenyl-3-(1H-pyrrol-1-yl)-2,3-dihydro-1H-indene-2-carboxylic acid | C20H17NO2 | 详情 | 详情 |