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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.

〖作者〗

Bell, A.S.; Brown, D.; Terrett, N.K. (Pfizer Inc.)

〖参考〗

Bell, A.S.; Brown, D.; Terrett, N.K. (Pfizer Inc.); Pyrazolopyrimidinone antianginal agents. EP 0463756; JP 1994041133; US 5250534; US 5346901

〖出处〗

EP 0463756; JP 1994041133; US 5250534; US 5346901,,():

〖备注〗

〖来源〗

EP 0812845; JP 1998081688; JP 1999171879

〖合成路线〗

〖标题〗

Process for preparing sildenafil

〖合成方法〗

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.

〖作者〗

Dunn, P.J.; Wood, A.S. (Pfizer Inc.)

〖参考〗

Dunn, P.J.; Wood, A.S. (Pfizer Inc.); Process for preparing sildenafil. EP 0812845; JP 1998081688; JP 1999171879

〖出处〗

EP 0812845; JP 1998081688; JP 1999171879,,():

〖备注〗

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 癈.