Atrial fibrillation (AF) is the most prevalent arrhythmia, the incidence of which increases with age. It is estimated that 8% of all people over the age of 80 experience this type of abnormal heart rhythm and AF accounts for one-third of hospital admissions for cardiac rhythm disturbances. Over 2.2 million people are believed to have AF in the Unites States alone. Fuster, et al Circulation 2006 1 14 (7): e257-354. Although atrial fibrillation is often asymptomatic it may cause palpitations or chest pain. Prolonged atrial fibrillation often results in the
development of congestive heart failure and/or stroke. Heart failure develops as the heart attempts to compensate for the reduced cardiac efficiency while stroke may occur when thrombi form in the atria, pass into the blood stream and lodge in the brain. Pulmonary emboli may also develop in this manner.
U.S. Patent No. 5,223, 10 discloses alkylaminoalkyl derivatives of benzofuran, benzothiophene, indole and indolizine, processes for their preparation and compositions containing them. WO 2013/014480 discloses a process for manufacturing dronedarone comprising reduction of the compound of formula (II) to the compound of formula (I) as shown below:
WO 2012/127174 discloses a process involving a Fries rearrangement converting, for example, the compound of formula (8) to the compound of formula (9) followed by coupling of the compound of formula (9) and dibutylamino propyl chloride to afford the compound of formula (I).
(8) (9)
, N(n-Bu)2
European patent application EP2617718A1 discloses processes for preparing dronedarone comprising reacting the intermediate
where L is a leaving group with dibutylaminopropanol.
The above disclosures notwithstanding, there remains a need for alternate or improved processes for preparing dronedarone.
SUMMARY OF THE DISCLOSURE
The present disclosure provides a process for making dronedarone of formula I
or a pharmaceutically acceptable salt thereof, comprising the steps of:
a. reacting the compound of formula (1) with the compound of formula (2) in the presence of a Lewis acid and a suitable solvent to form the compound of formula (3) as shown below:
b. reacting the compound of formula (3) with N-benzylmethanesulfonamide
(MeSC^NHBn) in the presence of a suitable catalyst and a suitable solvent to form the compound of formula (4) as shown below:
c. reacting the compound of formula (4) with dibutylaminopropanol in the presence of a suitable base and a suitable solvent to form the compound of formula (5) as shown below:
(4) (5)
d. reacting the compound of formula (5) with a suitable deprotecting agent to form the compound of formula (I) as shown below:
The present disclosure also provides a process for making dronedarone acid addition salt
the steps of:
a. reacting the compound of formula (1) with the compound of formula (2) in the presence of a Lewis acid and a suitable solvent to form the compound of formula (3) as shown below:
b. reacting the compound of formula (3) with N-benzylmethanesulfonamide (CH3S02NHBn) in the presence of a suitable catalyst and a suitable solvent to form the compound of formula (4) as shown below:
c. reacting the compound of formula (4) with dibutylaminopropanol in the presence of a suitable base and a suitable solvent to form the compound of formula (5) as shown below:
d. reacting the compound of formula (5) with a suitable deprotecting agent to form the compound of formula (I) as shown below:
and
e. reacting the compound of formula (I) with a suitable acid (HA) and a suitable solvent to afford the acid salt of the compound of formula (I) as shown below:
The present disclosure also provides a process for making dronedarone of formula (I)
or a pharmaceutically acceptable salt thereof, comprising the steps of:
a. reacting the compound of formula (1) with the compound of formula (2) in the presence of a Lewis acid and a suitable solvent to form the compound of formula (3) as shown below
b. reacting the compound of formula (3) with Boc-protected methanesulfonamide and a suitable catalyst and a suitable solvent to afford the Boc-protected compound of formula (6) as shown below:
c. reacting compound of formula (6) with dibutylaminopropanol, a suitable base and a suitable solvent to afford the compound of formula (7) as shown below:
d. reacting the compound of formula (7) with a suitable acid and a suitable solvent to afford the compound of formula (I) as shown below:
e. optionally reacting the compound of formula (7) with a sufficient amount of a suitable acid to form the acid salt of the compound of formula (I) as shown below:
One advantage of the present disclosure is that it obviates certain mutagenic impurities observed with the process disclosed in United States patent No. 5,223,510. One of skill in the art is aware by virtue of the present disclosure that other protecting groups may be used in place of the protecting groups (benzyl or Boc) disclosed herein.
An object of the present disclosure is also the provision of intermediate compounds useful for making the compound of formula (I) or salts thereof. Thus, in one embodiment the present disclosure provides a compound of formula (4)
a salt thereof.
In another embodiment the present disclosure provides a compound of formula (6)
(6)
In yet another embodiment, the present disclosure provides a compound of formula (7)
or a salt thereof.
"Droned arone" is described in U.S. Patent 5,223,510. Dronedarone refers to the chemical compound, N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)methanesulfonamide. The base form of dronedarone has the following chemical formula:
