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【结 构 式】 
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【分子编号】31769 【品名】2-(3-chloro-4-methoxyphenyl)acetyl chloride 【CA登记号】 |
【 分 子 式 】C9H8Cl2O2 【 分 子 量 】219.06672 【元素组成】C 49.35% H 3.68% Cl 32.37% O 14.61% |
合成路线1
该中间体在本合成路线中的序号：(II)Acylation of the chiral aminodiol (I) with acid chloride (II) gave amide (III), which was reduced to amine (IV) by means of NaBH4 and AcOH. Cyclization of (IV) using HF and BF3 then produced benzazepine (V). Reductive N-methylation of (V) was accomplished by the Eschweiler-Clarke procedure using formaldehyde and formic acid. The resulting aminoalcohol (VI) was converted to mesylate (VII) and subsequently treated with NaCN in DMSO to generate nitrile (VIII). Acid hydrolysis of the nitrile (VIII) to the corresponding carboxylic acid (IX), followed by treatment with SOCl2 afforded acid chloride (X), which was cyclized in the presence of AlCl3 to produce the tetracyclic system (XI). The ketone function of (XI) was then reduced to (XII) using BH3 and trifluoroacetic acid. Further demethylation of the methyl ether of (XII) with either BBr3 or AlCl3 yielded the title compound.
| 【1】 Wu, G.; et al.; Amino diol based asymetric syntheses of a fused benzazepine as a selective D1 dopamine receptor. Org Process Res Dev 1997, 1, 5, 359. |
| 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) | 31768 | (1S,2S)-2-amino-1-phenyl-1,3-propanediol | 28143-91-1 | C9H13NO2 | 详情 | 详情 |
| (II) | 31769 | 2-(3-chloro-4-methoxyphenyl)acetyl chloride | C9H8Cl2O2 | 详情 | 详情 | |
| (III) | 31770 | 2-(3-chloro-4-methoxyphenyl)-N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]acetamide | C18H20ClNO4 | 详情 | 详情 | |
| (IV) | 31771 | (1S,2S)-2-[(3-chloro-4-methoxyphenethyl)amino]-1-phenyl-1,3-propanediol | C18H22ClNO3 | 详情 | 详情 | |
| (V) | 31772 | [(1R,2R)-7-chloro-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]methanol | C18H20ClNO2 | 详情 | 详情 | |
| (VI) | 31773 | [(1R,2R)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]methanol | C19H22ClNO2 | 详情 | 详情 | |
| (VII) | 31774 | (4R,5R)-8-chloro-3-methyl-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl methyl ether; (1R,2R)-7-chloro-8-methoxy-3-methyl-2-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine | C22H28ClNO2S | 详情 | 详情 | |
| (VIII) | 31775 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetonitrile | C20H21ClN2O | 详情 | 详情 | |
| (IX) | 31776 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetic acid | C20H22ClNO3 | 详情 | 详情 | |
| (X) | 31777 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]acetyl chloride | C20H21Cl2NO2 | 详情 | 详情 | |
| (XI) | 31778 | (3aS,9bS)-12-chloro-11-methoxy-3-methyl-1,2,3,3a,4,9b-hexahydro-5H-naphtho[1,2-a][3]benzazepin-5-one | C20H20ClNO2 | 详情 | 详情 | |
| (XII) | 31779 | (3aS,9bR)-12-chloro-11-methoxy-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepine; (3aS,9bR)-12-chloro-3-methyl-2,3,3a,4,5,9b-hexahydro-1H-naphtho[1,2-a][3]benzazepin-11-yl methyl ether | C20H22ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)In a different approach, starting from the chiral oxazolidine (XV), conversion to the corresponding mesylate and further displacement by NaCN afforded nitrile (XVI). Acid hydrolysis of the oxazolidine (XVI) and esterification with MeOH produced aminoester (XVII). This was acylated with acid chloride (II) to yield a mixture of amide-ester (XVIII) and amide-lactone (XIX). Reduction of this mixture with NaBH4 and AcOH furnished diol (XX), which was cyclized employing BF3 in methanesulfonic acid. The resulting benzazepine (XXI) was reductively methylated under Schweiler-Clarke conditions to give (XIV). Finally, chlorination with PCl5, followed by cyclization and demethylation with AlCl3 provided the title compound.
| 【1】 Wu, G.; et al.; Amino diol based asymetric syntheses of a fused benzazepine as a selective D1 dopamine receptor. Org Process Res Dev 1997, 1, 5, 359. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 31769 | 2-(3-chloro-4-methoxyphenyl)acetyl chloride | C9H8Cl2O2 | 详情 | 详情 | |
| (XIV) | 31781 | 2-[(1R,2S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]-1-ethanol | C20H24ClNO2 | 详情 | 详情 | |
| (XV) | 31782 | [(4S,5S)-2-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-4-yl]methanol | 53732-41-5 | C11H13NO2 | 详情 | 详情 |
| (XVI) | 31783 | 2-[(4S,5S)-2-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-4-yl]acetonitrile | C12H12N2O | 详情 | 详情 | |
| (XVII) | 31784 | methyl (3S,4S)-3-amino-4-hydroxy-4-phenylbutanoate | C11H15NO3 | 详情 | 详情 | |
| (XVIII) | 31785 | methyl (3S,4S)-3-[[2-(3-chloro-4-methoxyphenyl)acetyl]amino]-4-hydroxy-4-phenylbutanoate | C20H22ClNO5 | 详情 | 详情 | |
| (XIX) | 31786 | 2-(3-chloro-4-methoxyphenyl)-N-[(2R,3S)-5-oxo-2-phenyltetrahydro-3-furanyl]acetamide | C19H18ClNO4 | 详情 | 详情 | |
| (XX) | 31787 | (1S,2S)-2-[(3-chloro-4-methoxyphenethyl)amino]-1-phenyl-1,4-butanediol | C19H24ClNO3 | 详情 | 详情 | |
| (XXI) | 31788 | 2-[(1R,2S)-7-chloro-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-yl]-1-ethanol | C19H22ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)A further procedure for the synthesis of the title compound has been reported. The compound was prepared by alkylation of paroxetine acetate (I) with 2-chloro-4'-fluoroacetophenone (II) in the presence of NaHCO3 in refluxing EtOH, followed by conversion to the hydrochloride salt with HCl in Et2O.
| 【1】 Sacristan, A.; Ortiz, J.A.; Foguet, R.; Gubert, S. (Ferrer Internacional SA); Process for preparing (-)-trans-N-p-fluorobenzoylmethyl-4-(p-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]piperidine. US 5973155; WO 9731915 . |