Process for the preparation of dronedarone
View Patent ↗The present invention provides, according to an aspect thereof, a novel process for the preparation of dronedarone [1] and pharmaceutically acceptable salts thereof. According to a preferred embodiment, the process comprises N-acetylating of p-anisidine or p-phenetidine with acetic anhydride, reacting of the obtained N-(4-alkoxyphenyl)acetamide with 2-bromohexanoyl chloride or bromide in the presence of aluminum chloride or bromide to obtain N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6 a ], converting the compound [6 a ] into 2-butyl-5-benzofuranamine hydrochloride [12 a ] and subsequently converting [12 a ] into [1] or pharmaceutically acceptable salts thereof. In accordance with another aspect of this invention, there are provided novel intermediates, inter alia the novel compounds [6 a ] and [12 a ]. The novel intermediates of the present invention are stable, solid compounds, obtainable in high yields, which can be easily purified by crystallization and stored for long periods of time.
1. A process for preparing dronedarone [1]
or a pharmaceutically acceptable salt thereof, which process comprises the steps of:
(a) reacting a compound of formula [3] with 2-bromohexanoyl chloride or bromide in the presence of aluminum chloride or bromide to obtain a compound of formula [6]:
wherein R 1 is methyl or ethyl; and R 2 is selected from the group consisting of alkyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy;
(b) converting the compound [6] obtained in step (a) above into the compound of formula [9]
(c) dehydrating and N-deprotecting the compound of formula [9] obtained in step (b) above in an aqueous solution of HX 4 , wherein HX 4 is selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid and p-toluenesulfonic acid, to obtain the solid acid addition salt of 2-butyl-5-benzofuranamine [12]
(d) optionally, preparing 2-butyl-5-benzofuranamine free base from the acid addition salt of 2-butyl-5-benzofuranamine [12] obtained in step (c) above;
(e) reacting the 2-butyl-5-benzofuranamine free base obtained in step (d) above or the acid addition salt of 2-butyl-5-benzofuranamine [12] obtained in step (c) with an agent selected from the group consisting of methanesulfonic anhydride and methanesulfonyl chloride or fluoride to obtain N- (2-butyl-5-benzofuranyl)methanesulfonamide [14]
(f) Friedel-Crafts acylating of N (2-butyl-5-benzofuranyl)methanesulfonamide [14] obtained in step (e) above with 4- (3-dibutylaminopropoxy)benzoyl chloride hydrochloride [15]
to obtain dronedarone [1] or a pharmaceutically acceptable salt thereof.
2. The process of claim 1 wherein compound 6 is converted into the compound of formula [9] in step (b) without isolating the intermediate compounds [7] and [8]:
3. The process of claim 1 wherein compound [12] is obtained in step (c) without isolating the intermediate compounds [10] and [11]:
4. The process of claim 1 , wherein R 2 is a methyl group.
5. The process of claim 1 , wherein HX 4 is hydrogen chloride.
6. A compound of formula [6]:
wherein R 2 is selected from the group consisting of alkyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy.
7. A compound of formula [7]:
wherein R 2 is selected from the group consisting of alkyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy.
8. A compound of formula [9]:
wherein R 2 is selected from the group consisting of alkyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy.
9. A compound of formula [10]:
wherein R 2 is selected from the group consisting of alkyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy.
10. The compound of claim 6 wherein R 2 is methyl.
11. The compound of claim 7 wherein R 2 is methyl.
12. The compound of claim 8 wherein R 2 is methyl.
13. The compound of claim 9 wherein R 2 is methyl.
14. A process according to claim 1 for the preparation of dronedarone [1] or apharmaceutically acceptable salt thereof:
such process comprising the steps of:
N-acetylating of p-anisidine or p-phenetidine with acetic anhydride, reacting of the obtained N-(4-alkoxyphenyl)acetamide with 2-bromohexanoyl chloride or bromide in the presence of aluminum chloride or bromide to obtain N-[3-(2-bromohexanoyl)-4-hydroxyphenyl] acetamide [6a], converting the compound [6] into 2-butyl-5-benzofuranamine hydrochloride [12a] and subsequently converting [12a] into [1] or a pharmaceutically acceptable salt thereof.
15. A compound of formula [6]: