【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 |