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【结 构 式】 
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【分子编号】19574 【品名】(4-carboxybutyl)(triphenyl)phosphonium chloride 【CA登记号】 |
【 分 子 式 】C23H24ClO2P 【 分 子 量 】398.868822 【元素组成】C 69.26% H 6.06% Cl 8.89% O 8.02% P 7.77% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of 4-amino-5-chloro-2-methoxybenzoic acid (I) with benzyl chloride (II) and NaHCO3 in refluxing water gives the N-benzyl protected compound (III), which is condensed with cis-4-amino-3-methoxypiperidine-1-carboxylic acid ethyl ester (IV) by means of methyl chloroformate and TEA in dichloromethane to yield the benzamide (V). The deprotection of (V) with KOH in refluxing isopropanol affords compound (VI) with a free piperidinic NH group that is acylated with 3-(4-fluorophenoxy)propyl chloride (VII) by means of Na2CO3 in refluxing methylisobutylketone to provide the protected adduct (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in hot methanol to give the target compound. Alternatively, the piperidine derivative (VI) is treated with p-toluenesulfonic acid in refluxing toluene and then debenzylated and simultaneously reductocondensed with 3-(4-fluorophenoxy)propionaldehyde (IX) by means of H2 over Pd/C in methanol to give the target compound.
| 【1】 Gutierrez Fuentes, L.G.; Process for the preparation of benzamides. ES 2019047 . |
| 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) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 49580 | 4-(benzylamino)-5-chloro-2-methoxybenzoic acid | C15H14ClNO3 | 详情 | 详情 | |
| (IV) | 19574 | (4-carboxybutyl)(triphenyl)phosphonium chloride | C23H24ClO2P | 详情 | 详情 | |
| (V) | 19581 | trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; | 27489-62-9 | C6H13NO | 详情 | 详情 |
| (VI) | 49582 | 4-(benzylamino)-5-chloro-2-methoxy-N-[(3S,4R)-3-methoxypiperidinyl]benzamide | C21H26ClN3O3 | 详情 | 详情 | |
| (VII) | 30524 | 3-chloropropyl 4-fluorophenyl ether; 1-(3-chloropropoxy)-4-fluorobenzene; 1-(4-Fluorophenoxy)-3-chloropropane | 1716-42-3 | C9H10ClFO | 详情 | 详情 |
| (VIII) | 49583 | 4-(benzylamino)-5-chloro-N-[(3S,4R)-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidinyl]-2-methoxybenzamide | C30H35ClFN3O4 | 详情 | 详情 | |
| (IX) | 49584 | 3-(4-fluorophenoxy)propanal | C9H9FO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)2-Iodo-6-(4-chlorophenylsulfonyl)amino-5,6,7,8-tetrahydro-naphthyl-1-carbaldehyde (I) was coupled with 3-(tributylstannyl-methyl)pyridine (II) in the presence of Pd(PPh3)4 in N-methylpyrrolidine (NMP) at 110 C to afford the pyridinylmethyl derivative (III). Subsequent coupling of (VI) with (4-carboxybutyl)triphenylphosphonium chloride (IV) in the presence of potassium tert-butoxide in THF at low temperature provided a mixture of E and Z hexenoic acids (V), from which the target (E) isomer was isolated by column chromatography.
| 【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381. |
| 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) | 19571 | 4-chloro-N-(5-formyl-6-iodo-1,2,3,4-tetrahydro-2-naphthalenyl)benzenesulfonamide | C17H15ClINO3S | 详情 | 详情 | |
| (II) | 19572 | 3-[(tributylstannyl)methyl]pyridine | C18H33NSn | 详情 | 详情 | |
| (III) | 19573 | 4-chloro-N-[5-formyl-6-(3-pyridinylmethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]benzenesulfonamide | C23H21ClN2O3S | 详情 | 详情 | |
| (IV) | 19574 | (4-carboxybutyl)(triphenyl)phosphonium chloride | C23H24ClO2P | 详情 | 详情 | |
| (V) | 19575 | (E)-6-[6-[[(4-chlorophenyl)sulfonyl]amino]-2-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]-5-hexenoic acid | C28H29ClN2O4S | 详情 | 详情 |