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【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

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.

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

 

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

 

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