Dronedarone hydrochloride, SR-33589B, -Drug Synthesis Database

【结构式】

【药物名称】Dronedarone hydrochloride, SR-33589B

【化学名称】2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-(methylsulfonamido)benzofuran hydrochloride

【CA登记号】141626-36-0 (free base)

【分子式】C₃₁H₄₅ClN₂O₅S

【分子量】593.2317

【开发单位】Sanofi-synthélabo (Originator)

【药理作用】Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, alpha-Adrenoceptor Antagonists, beta-Adrenoceptor Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

Treatment of 2-hydroxy-5-nitrobenzyl bromide (I) with triphenylphosphine in refluxing chloroform provides phosphonium bromide derivative (II), which is converted into 2-butyl-5-nitro benzofuran (IV) by first reaction with pentanoyl chloride (III) in refluxing chloroform in the presence of pyridine, followed by treatment with Et3N in refluxing toluene. Acylation of (IV) with anisoyl chloride (V) by means of tin tetrachloride in dichloroethane furnishes 2-butyl-3-(4-methoxy benzoyl)-5-nitro benzofuran (VI), whose methoxy group is then converted into an hydroxy group by treatment with aluminum chloride in refluxing dichloroethane, yielding hydroxy benzoyl derivative (VII). Condensation of (VII) with N,N-dibutyl-N-(3-chloropropyl)amine (VIII) by means of K2CO3 in refluxing butanone affords compound (IX), which is then hydrogenated over PtO2 in EtOH to give amino derivative (X). Finally, the target product is obtained by reaction of (X) with methanesulfonyl chloride and Et3N in dichloroethane and hydrochloride salt formation with HCl in AcOEt/ethyl ether.

参考文献中间体

【1】 Gubin, J.; Lucchetti, J.; Inion, H.; Chatelain, P.; Rosseels, G.; Kilenyi, S. (Sanofi-Synthélabo); Benzofuran derivs., benzothiophenes, indoles or indolizines, process for production and compsns. containing them. EP 0471609; FR 2665444; JP 1992316554; US 5223510 .

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)	50821	alpha-Bromo-4-nitro-o-cresol; Koshland's reagent; 2-Hydroxy-5-nitrobenzyl bromide	772-33-8	C₇H₆BrNO₃	详情	详情
(II)	50822	(2-hydroxy-5-nitrobenzyl)(triphenyl)phosphonium bromide		C₂₅H₂₁BrNO₃P	详情	详情
(III)	15116	pentanoyl chloride; valeryl chloride	638-29-9	C₅H₉ClO	详情	详情
(IV)	50823	2-butyl-5-nitro-1-benzofuran		C₁₂H₁₃NO₃	详情	详情
(V)	22671	4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride	100-07-2	C₈H₇ClO₂	详情	详情
(VI)	50824	(2-butyl-5-nitro-1-benzofuran-3-yl)(4-methoxyphenyl)methanone		C₂₀H₁₉NO₅	详情	详情
(VII)	50825	(2-butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxyphenyl)methanone		C₁₉H₁₇NO₅	详情	详情
(VIII)	50826	N,N-dibutyl-N-(3-chloropropyl)amine; N-butyl-N-(3-chloropropyl)-1-butanamine	36421-15-5	C₁₁H₂₄ClN	详情	详情
(IX)	50827	(2-butyl-5-nitro-1-benzofuran-3-yl)[4-[3-(dibutylamino)propoxy]phenyl]methanone		C₃₀H₄₀N₂O₅	详情	详情
(X)	50828	(5-amino-2-butyl-1-benzofuran-3-yl)[4-[3-(dibutylamino)propoxy]phenyl]methanone		C₃₀H₄₂N₂O₃	详情	详情

合成路线2

参考文献中间体

【1】 Gutman AL, Nisnevich G, Yudovitch L.2003.Process for the perparation of dronedarone. WO 2003/040120; US 5223510; WO 9717346.

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)	10251	methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate	99-76-3	C₈H₈O₃	详情	详情
(II)	12581	1,3-Dibromopropane	109-64-8	C₃H₆Br₂	详情	详情
(III)	67102	methyl 4-(3-bromopropoxy)benzoate	135998-88-8	C₁₁H₁₃BrO₃	详情	详情
(IV)	67103	methyl 4-(4-(dibutylamino)butyl)benzoate		C₂₀H₃₃NO₂	详情	详情
(V)	67104	4-(3-(dibutylamino)propoxy)benzoic acid hydrochloride		C₁₈H₂₉NO₃.HCl	详情	详情
(VI)	67105	4-(3-(dibutylamino)propoxy)benzoyl chloride hydrochloride		C₁₈H₂₈ClNO₂.HCl	详情	详情
(VII)	10478	p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine	104-94-9	C₇H₉NO	详情	详情
(VIII)	67106	N-(4-methoxyphenyl)acetamide	51-66-1	C₉H₁₁NO₂	详情	详情
(IX)	67107	2-bromohexanoyl chloride	42768-46-7	C₆H₁₀BrClO	详情	详情
(X)	67108	N-(2-(2-bromohexanoyl)-4-hydroxyphenyl)acetamide		C₁₄H₁₈BrNO₃	详情	详情
(XI)	67109	N-(2-butyl-3-hydroxy-2,3-dihydrobenzofuran-6-yl)acetamide		C₁₄H₁₉NO₃	详情	详情
(XII)	67110	N-(2-butylbenzofuran-6-yl)acetamide		C₁₄H₁₇NO₂	详情	详情
(XIII)	67111	2-butylbenzofuran-6-amine hydrochloride		C₁₂H₁₅NO.HCl	详情	详情
(XIV)	67112	N-(2-butylbenzofuran-6-yl)methanesulfonamide		C₁₃H₁₇NO₃S	详情	详情

合成路线3

参考文献中间体

【1】 Fino N, Leroy C.2002.A process for the preparation of 2-butyl [methanesulfonamido] benzofuran as an intermediate for the synthesis of dronedarone.WO 2002048132.

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)	50823	2-butyl-5-nitro-1-benzofuran		C₁₂H₁₃NO₃	详情	详情
(II)	67113	2-butylbenzofuran-6-amine		C₁₂H₁₅NO	详情	详情
(III)	67112	N-(2-butylbenzofuran-6-yl)methanesulfonamide		C₁₃H₁₇NO₃S	详情	详情
(IV)	10251	methyl 4-hydroxybenzoate; Methyl p-hydroxybenzoate	99-76-3	C₈H₈O₃	详情	详情
(V)	50826	N,N-dibutyl-N-(3-chloropropyl)amine; N-butyl-N-(3-chloropropyl)-1-butanamine	36421-15-5	C₁₁H₂₄ClN	详情	详情
(VI)	67114	methyl 4-(3-(dibutylamino)propoxy)benzoate	36421-15-5	C₁₉H₃₁NO₃	详情	详情
(VII)	67105	4-(3-(dibutylamino)propoxy)benzoyl chloride hydrochloride		C₁₈H₂₈ClNO₂.HCl	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)