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【结 构 式】 
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【分子编号】21191 【品名】4-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]amino)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide 【CA登记号】 |
【 分 子 式 】C22H32N6O5S 【 分 子 量 】492.59952 【元素组成】C 53.64% H 6.55% N 17.06% O 16.24% S 6.51% |
合成路线1
该中间体在本合成路线中的序号：(VII)A more efficient process for preparing clinical-grade sildenafil has been described: The reaction of 2-ethoxybenzoic acid (I) with SOCl2 and ClSO3H gives 5-(chlorosulfonyl)-2-ethoxybenzoic acid (II), which is condensed with 1-methylpiperazine (III) by means of triethylamine in water yielding 2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (IV). The condensation of (IV) with 4-amino-1-methyl-3-propylpyrazole-5-carboxamide (V), obtained by reduction of the corresponding 4-nitro compound (VI) with H2 over Pd/C in ethyl acetate, by means of carbonyldiimidazole (CDI) in refluxing ethyl acetate affords the corresponding amide (VII), which is finally cyclized by means of potassium tert-butoxide in refluxing tert-butanol. Other cyclizing agents such as KOH, KHCO3, BaO, sodium ethoxide, sodium tert-butoxide, NaH, NaNH2, sodium decyloxide, sodium cyclohexylamide, sodium 4-methylpiperazide, Cs2CO3, magnesium ethoxide, barium ethoxide, cupric ethoxide, aluminum tert-butoxide, titanium ethoxide, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), KF or several Lewis acids, as well as other solvents such as methanol, ethanol, tert-amyl alcohol, 1-methylcyclohexanol, THF, 1,4-dioxan, 1,2-dimethoxyethane, 3,7-dimethyloctan-3-ol, DMSO, pyridine, acetonitrile, or methyl isobutyl ketone have also been used; the reaction temperature is normally 100 C.
| 【1】 Dale, D.J.; et al.; The chemical development of the commercial route to sildenafil: A case history. Org Process Res Dev 2000, 4, 1, 17. |
| 【2】 Dunn, P.J.; Wood, A.S. (Pfizer Inc.); Process for preparing sildenafil. EP 0812845; JP 1998081688; JP 1999171879 . |
| 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) | 21185 | 2-ethoxybenzoic acid | 134-11-2 | C9H10O3 | 详情 | 详情 |
| (II) | 21186 | 5-(chlorosulfonyl)-2-ethoxybenzoic acid | 200575-16-2 | C9H9ClO5S | 详情 | 详情 |
| (III) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (IV) | 21188 | 2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid | 194602-23-8 | C14H20N2O5S | 详情 | 详情 |
| (V) | 15626 | 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide; 4-Nitro-1-methyl-3-propyl-5-pyrazolecarboxamide | 139756-01-8 | C8H12N4O3 | 详情 | 详情 |
| (VI) | 15627 | 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide | 139756-02-8 | C8H14N4O | 详情 | 详情 |
| (VII) | 21191 | 4-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]amino)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide | C22H32N6O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)Synthesis of sildenafil: Reaction of 5-(chlorosulfonyl)-2-hydroxybenzoic acid (XIV) with 1-methylpiperazine (XV) by means of DIEA gives the sulfonamide (XVI), which is treated with diethyl sulfate yielding 2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (XVII). The activation of (XVII) with a polymer-supported 1-hydroxybenzotriazole (HOBt) variant (XVIII) and bromotris(pyrrolidino)phosphonium (PyBrOP) as catalyst affords the activated ester (XIX), which is condensed with the aminopyrazole intermediate (XIII), and treated with the methyl isocyanate resin (X) in order to eliminate the excess of aminopyrazole (XIII), to provide the diamide (XX). Finally, the cyclization and dehydration to sildenafil are performed by microwave irradiation of an ethanolic solution of compound (XX) containig a catalytic amount of NaOEt.
| 【1】 Baxendale, I.R.; Ley, S.V.; Polymer-supported reagents for multi-step organic synthesis: Application to the synthesis of sildenafil. Bioorg Med Chem Lett 2000, 10, 17, 1983. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (XIII) | 15627 | 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide | 139756-02-8 | C8H14N4O | 详情 | 详情 |
| (XIV) | 44346 | 5-(chlorosulfonyl)-2-hydroxybenzoic acid | C7H5ClO5S | 详情 | 详情 | |
| (XV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVI) | 44347 | 2-hydroxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid | C12H16N2O5S | 详情 | 详情 | |
| (XVII) | 21188 | 2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid | 194602-23-8 | C14H20N2O5S | 详情 | 详情 |
| (XVIII) | 44348 | 1-hydroxy-1H-1,2,3-benzotriazole-6-carbaldehyde | C7H5N3O2 | 详情 | 详情 | |
| (XIX) | 44349 | 1-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]oxy)-1H-1,2,3-benzotriazole-6-carbaldehyde | C21H23N5O6S | 详情 | 详情 | |
| (XX) | 21191 | 4-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]amino)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide | C22H32N6O5S | 详情 | 详情 |