Sildenafil citrate, UK-92480-10, UK-92480(free base), Penegra, Patrex, Wan Ai Ke, Viagra, -Drug Synthesis Database

【结构式】

【药物名称】Sildenafil citrate, UK-92480-10, UK-92480(free base), Penegra, Patrex, Wan Ai Ke, Viagra

【化学名称】5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one citrate

【CA登记号】171599-83-0, 139755-83-2 (free base)

【分子式】C₂₈H₃₈N₆O₁₁S

【分子量】666.71266

【开发单位】Pfizer (Orphan Drug), Pfizer (Originator), Bagó(Licensee)

【药理作用】CARDIOVASCULAR DRUGS, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Hypertension, Treatment of, Pulmonary Hypertension, Treatment of, RENAL-UROLOGIC DRUGS, Treatment of Erectile Dysfunction, Treatment of Female Sexual Dysfunction, Treatment of Male Sexual Dysfunction, Vasodilators, Phosphodiesterase V (PDE5A) Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

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.

参考文献中间体

【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

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.

参考文献中间体

【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

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).

参考文献中间体

【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

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.

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)