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【结 构 式】 
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【分子编号】15627 【品名】4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide 【CA登记号】139756-02-8 |
【 分 子 式 】C8H14N4O 【 分 子 量 】182.22552 【元素组成】C 52.73% H 7.74% N 30.75% O 8.78% |
合成路线1
该中间体在本合成路线中的序号：(VI)The methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester (I) with hot dimethyl sulfate gives 1-methyl-3-propylpyrazole-5-carboxylic acid ethyl ester (II), which is hydrolyzed with aqueous NaOH to the corresponding free acid (III). The nitration of (III) with oleum/fuming nitric acid yields the 4-nitro derivative (IV), which is treated first with refluxing SOCl2 and then with NH4OH to afford the corresponding carboxamide (V). The reduction of the nitro group of (V) with SnCl2 dihydrate in refluxing ethanol gives 4-amino-1-methyl-3-propylpyrazole-5-carboxamide (VI), which is acylated with 2-ethoxybenzoyl chloride (VII) by means of triethylamine in dichloromethane yielding 4-(2-ethoxybenzamido)-1-methyl-3-propylpyrazole-5-carboxamide (VIII). The cyclization of (VIII) by means of NaOH and H2O2 in refluxing ethanol affords 5-(2-ethoxyphenyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d] pyrimidin-7-one (IX), which is sulfonated with chlorosulfonic acid affording the chlorosulfonyl derivative (X). Finally, this compound is condensed with 1-methylpiperazine in ethanol at room temperature.
| 【1】 Martel, A.M.; Graul, A.; Rabasseda, X.; Castaner, R.M.; Sildenafil. Drugs Fut 1997, 22, 2, 138. |
| 【2】 Terrett, N.K.; Bell, A.S.; Brown, D.; Ellis, P.; Sildenafil (Viagra(TM)), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg Med Chem Lett 1996, 6, 15, 1819-24. |
| 【3】 Bell, A.S.; Brown, D.; Terrett, N.K. (Pfizer Inc.); Pyrazolopyrimidinone antianginal agents. EP 0463756; JP 1994041133; US 5250534; US 5346901 . |
| 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) | 15622 | ethyl 3-propyl-1H-pyrazole-5-carboxylate | C9H14N2O2 | 详情 | 详情 | |
| (II) | 15623 | ethyl 1-methyl-3-propyl-1H-pyrazole-5-carboxylate | C10H16N2O2 | 详情 | 详情 | |
| (III) | 15624 | 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid | C8H12N2O2 | 详情 | 详情 | |
| (IV) | 15625 | 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid | C8H11N3O4 | 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) | 15628 | 2-ethoxybenzoyl chloride | 42926-52-3 | C9H9ClO2 | 详情 | 详情 |
| (VIII) | 15629 | 4-[(2-ethoxybenzoyl)amino]-1-methyl-3-propyl-1H-pyrazole-5-carboxamide | C17H22N4O3 | 详情 | 详情 | |
| (IX) | 15630 | 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(2-ethoxyphenyl)-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-one | 139756-21-1 | C17H20N4O2 | 详情 | 详情 |
| (X) | 15631 | 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride | C17H19ClN4O4S | 详情 | 详情 | |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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3
该中间体在本合成路线中的序号：(XIII)Synthesis of the aminopyrazole intermediate (XIII): The reaction of butanal (I) with methylhydrazine (II) in dichloromethane in the presence of MgSO4 gives the corresponding hydrazide (III), which is alkylated with ethyl bromoacetate (IV) by means of the polymer-supported base 2-(tert-butylimino)-2-(diethylamino)-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (V) and polymer-supported methylamine (VI) to yield the hydrazino ester (VII). Treatment of compound (VII) with an ion exchange tetramethylammonium cyanide resin (VIII) in refluxing ethanol containing a catalytic amount of HOAc affords the adduct (IX), which is dehydrogenated with Pd/C/cyclopentene or MnO2 and treated with a polymer-supported ethyl isocyanate resin (X) in order to eliminate the unreacted product, providing the hydrazone (XI). Cyclization of (XI) by means of PS-BEMP (V) in ethanol gives 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid ethyl ester (XII), which is finally treated with ammonia in methanol to afford the desired pyrazolecarboxamide intermediate (XIII).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (II) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (III) | 44339 | butanal N-methylhydrazone | C5H12N2 | 详情 | 详情 | |
| (IV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (V) | 44344 | N-(tert-butyl)-N-[2-(diethylamino)-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-ylidene]amine; 2-(tert-butylimino)-N,N-diethyl-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-amine | C13H31N4P | 详情 | 详情 | |
| (VI) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (VII) | 44340 | ethyl 2-[2-[(E)butylidene]-1-methylhydrazino]acetate | C9H18N2O2 | 详情 | 详情 | |
| (VIII) | 44345 | N,N,N-trimethylmethanaminium cyanide | C5H12N2 | 详情 | 详情 | |
| (IX) | 44341 | ethyl 2-[2-(1-cyanobutyl)-1-methylhydrazino]acetate | C10H19N3O2 | 详情 | 详情 | |
| (X) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (XI) | 44342 | ethyl 2-[2-[(Z)-1-cyanobutylidene]-1-methylhydrazino]acetate | C10H17N3O2 | 详情 | 详情 | |
| (XII) | 44343 | ethyl 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylate | C10H17N3O2 | 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 |
合成路线4
该中间体在本合成路线中的序号：(XIII)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 |
合成路线5
该中间体在本合成路线中的序号：(III)The reaction of 2-propoxybenzoic acid (I) with SOCl2 in refluxing dichloromethane gives the acyl chloride (II), which is condensed with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (III) by means of TEA and DMAP in dichloromethane to yield the carboxamide (IV). The sulfonation of (IV) with chlorosulfonic acid affords the benzenesulfonyl chloride (V), which is treated with 2-(1-methylpyrrolidin-2-yl)ethylamine (VI) in dichloromethane to afford the sulfonamide (VII). Finally, this compound is cyclized by means of tBu-OK in refluxing tert-butanol to provide the target pyrazolo-pyrimidininone.
| 【1】 Kim, S.-H.; Chang, M.-S.; Kim, D.-S.; Yoo, M.-H.; Kim, W.-B.; Bae, C.-J.; Kim, Y.-D.; Kim, E.-H. (Dong-A Pharmaceutical Co., Ltd.); A process for preparing pyrazolopyrimidinone derivs. for the treatment of impotence. WO 0198304 . |
| 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) | 53952 | 2-n-Propoxybenzoic acid | 2100-31-4 | C10H12O3 | 详情 | 详情 |
| (II) | 53953 | 2-propoxybenzoyl chloride | C10H11ClO2 | 详情 | 详情 | |
| (III) | 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 |
| (IV) | 50253 | 1-methyl-4-[(2-propoxybenzoyl)amino]-3-propyl-1H-pyrazole-5-carboxamide | C18H24N4O3 | 详情 | 详情 | |
| (V) | 50254 | 3-([[5-(aminocarbonyl)-1-methyl-3-propyl-1H-pyrazol-4-yl]amino]carbonyl)-4-propoxybenzenesulfonyl chloride | C18H23ClN4O5S | 详情 | 详情 | |
| (VI) | 53954 | 2-(2-Aminoethyl)-1-methylpyrrolidine | n/a | C7H16N2 | 详情 | 详情 |
| (VII) | 53955 | 1-methyl-4-{[5-({[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-2-propoxybenzoyl]amino}-3-propyl-1H-pyrazole-5-carboxamide | C25H38N6O5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)The reaction of 5-(chlorosulfonyl)-2-propoxybenzoic acid (I) with 2-(1-methylpyrrolidin-2-yl)ethylamine (II) in acetone gives the sulfonamide (III), which is treated with 2,4,6-trichlorobenzozyl chloride (IV) and TEA to afford the active mixed anhydride (V). The condensation of (V) with 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (VI) in dichloromethane provides the corresponding carboxamide (VII). Finally, this compound is cyclized by means of tBu-OK in refluxing tert-butanol to furnish the target pyrrolo-pyrimidinone.
| 【1】 Kim, S.; Kim, H.; Kim, D.S.; Chang, M.S.; Yoo, M.; Lim, J.I.; Ahn, B.O.; Kim, W.; Kim, I.Y.; Lim, T.K.; Kang, K.K.; Son, M.; Doh, M.; Shim, H.; Oh, T.; Kim, D.G. (Dong-A Pharmaceutical Co., Ltd.); Pyrazolopyrimidinone derivs. for the treatment of impotence. EP 1129093; WO 0027848 . |
| 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) | 53956 | 5-(chlorosulfonyl)-2-propoxybenzoic acid | C10H11ClO5S | 详情 | 详情 | |
| (II) | 53954 | 2-(2-Aminoethyl)-1-methylpyrrolidine | n/a | C7H16N2 | 详情 | 详情 |
| (III) | 53957 | 5-({[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-2-propoxybenzoic acid | n/a | C17H26N2O5S | 详情 | 详情 |
| (IV) | 25718 | 2,4,6-trichlorobenzoyl chloride | 4136-95-2 | C7H2Cl4O | 详情 | 详情 |
| (V) | 53958 | 5-({[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-2-propoxy-1-benzenecarboxylic 2,4,6-trichloro-1-benzenecarboxylic anhydride | n/a | C24H27Cl3N2O6S | 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) | 53955 | 1-methyl-4-{[5-({[2-(1-methyl-2-pyrrolidinyl)ethyl]amino}sulfonyl)-2-propoxybenzoyl]amino}-3-propyl-1H-pyrazole-5-carboxamide | C25H38N6O5S | 详情 | 详情 |