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CHAPTER-I
An improved process for the preparation
of Dronedarone Hydrochloride
Introduction
10
Introduction
Atrial fibrillatio (AF or Afbi) is the most common cardiac rhythm disturbance and
is responsible for substantial morbidity, requiring hospitalization. It is growing
like an epidemic in western countries with an estimated prevalence of 3.8% of the
population aged over 60 years and 9% in respect of population aged over 80
years.1 It is expected to affect 30 million North Americans and Europeans by
2050.2
In AF, the normal electrical impulses usually originate in the roots of the
pulmonary veins, leading to irregular conduction of impulses to the ventricles
which generate the heartbeats. AF may be treated with medication and there are
two major treatment strategies available i.e. Rate control and Rhythm control.3
Rate control lowers the heart rate closer to normal; usually 60 to 100 bpm,
without trying to convert to a regular rhythm. This can be done with:
Beta blockers (preferably the “cardioselective” beta blockers such as
Metoprolol, Atenolol, Bisoprolol, Nebivolol).
Non-dihydropyridine calcium channel blockers (i.e. Diltiazem or
Verapamil).
Cardiac glycosides (i.e. Digoxin–which have limited use i.e. only
given to sedentary elderly patient).
Rhythm control is also called „Cardioversion‟ which is a non-invasive conversion
of an irregular heartbeat to a normal heartbeat using electrical or chemical means.
Electrical cardioversion involves the restoration of normal heart
rhythm through the application of Direct current (D.C.) electrical
shock.
Chemical cardioversion is performed with drugs, such as
Procainamide, Dofetilide, Idutilibe, Propafenone, Amiodarone and
Dronedarone.
11
History of Dronedarone Hydrochloride
Amiodarone (1; Figure–1), a benzofuran derivative synthesized in 1962 as a
coronary vasodilator, is now recognized as one of the most effective drugs in the
treatment of both atrial and ventricular arrhythmias.4
It is a multi channel blocker
and exerts a very complex electro pharmacologic effects, including classes I, II,
III and IV antiarrhythmic actions, with marked difference between short–term and
long–term effects.5 Chronic use of Amiodarone and its active metabolite
desethyl–amiodarone can cause adverse effects on thyroid such as
hypothyroidism or thyrotoxicosis, pulmonary toxicity and hepatic toxicity. 3, 6
Amiodarone is an iodinated benzofuran derivative (as seen in Figure–1). Due to
presence of the iodo–substituent, it is lipophilic and have a long half–life up to
100 days and causes thyroid dysfunction and accumulation in adipose tissue and
other organs like liver, lung, cornea, skin.2, 7–11
Figure−1
O
O
O
N R
I
I
1
R = Et, Amiodarone, R = H, Desethyl amiodarone
Since most of the unfavourable properties of Amiodarone are due to the presence
of iodine functionality, to improve the safety and tolerability, several non–
iodinated benzofuran derivatives have been synthesised. Of these modified
analogues, Dronedarone is the most advanced candidate in clinical development.
12
Structure of Dronedarone Hydrochloride
Dronedarone Hydrochloride (2; Figure–2) is a white fine powder, which is
practically insoluble in water and freely soluble in DCM, Chloroform and
methanol. Its empirical formula is C31H44N2O5S.HCl with a relative molecular
weight 593.2. Structure of Dronedarone Hydrochloride is provided in figure−2.
Figure−2
O
O
O
NHS
O O
N .HCl
Dronedarone Hydrochloride (2)
Dronedarone Hydrochloride (2) is a modified synthetic analogue of Amiodarone
with two molecular changes; i.e., it lacks the iodine functionality of Amiodarone
but has an additional sulphonamide group placed on benzofuran ring which
decreases lipophilicity, resulting in a shorter life-time and lower tissue
accumulation.
Dronedarone Hydrochloride is a potent blocker of multiple ion current and US
food and drug administration has approved it for treatment of AF on July 2, 2009.
13
Literature Review
A thorough literature search on Dronedarone Hydrochloride revealed that due to
the usefulness of this molecule, various synthetic process/routs have been
developed for its commercial production.
Gubin et al.12
[Product patent route, 1993]
Jean Gubin and co−workers synthesised Dronedarone Hydrochloride by using
2-hydroxy 5-nitro benzyl bromide (3) as key raw material which, on reaction with
triphenyl phosphine (TPP) in chloroform gave Wittig salt 4. Now condensation
of valeroyl chloride with Wittig salt 4 using pyridine as base, followed by
intramolecular Wittig reaction in toluene afforded nitro benzofuran derivative 5.
Friedel−Craft acylation reaction of nitro benzofuran 5 with p-anisoyl chloride, in
presence of stannic chloride yielded compound 6. Now demethylation was
achieved in EDC in presence of aluminium chloride to obtain intermediate 7
(Scheme−1).
Scheme−1
OH
Br
NO2
OH
PPh3
NO2
+
-Br
O
O2N
O
O2N
O
O
O
O2N
O
OH
3 4 5
6 7
a b
c d
Reagents and conditions: (a) TPP, CHCl3, reflux, 30 min; (b) i) valeroyl
chloride, pyridine, CHCl3, reflux, 2 h; ii) Et3N, toluene, reflux, 3 h;
(c) p-anisoyl chloride, SnCl4, DCM, 23 °C, 24 h; (d) AlCl3, EDC, reflux, 20 h.
14
Further condensation of chloro compound 42 with benzofuran 7 in MEK and
K2CO3 provided nitro compound 8. Reduction of nitro group to amine was
accomplished by catalytic hydrogenation in presence of PtO2 as catalyst in
ethanol and finally Dronedarone free base was synthesised using methane
sulfonyl chloride and Et3N in DCM. Purification of free base was performed by
column chromatography followed by hydrochloride salt formation in ethyl acetate
using hydrogen chloride in ether to furnish Dronedarone Hydrochloride (2) as
shown in scheme−2.
Scheme−2
O
O2N
O
OH
O
O2N
O
ON
O
O
ON
NH2
O
O
ON
NHS
O OO
O
ON
NHS
O O
.HCl
7 8
92 (free base) 2
a b
c d
N
Cl
+
42
Reagents and conditions: (a) K2CO3, MEK, reflux, 20 h; (b) PtO2/H2, EtOH,
RT, 20 min; (c) MsCl, Et3N, DCM, RT, 20 h; (d) HCl−ether, ethyl acetate, 45
min.
Generation of extensive amount of side product like TPPO during cyclization via
intramolecular Wittig reaction, use of class 1 solvent like EDC and formation of
mutagenic13
intermediate 7 were major disadvantages of this route.
15
Wolfgang M et a l 14
[synthesis of nitro benzofuran from methyl salicylate]
Wolfgang M. reported an alternative synthesis of nitro benzofuran derivative 5
exploiting methyl salicylate (10) as raw material which was condensed with
methyl-2-bromohexanoate (43) in acetonitrile and K2CO3 was used as base to
obtain diester compound 11 which on saponification with NaOH in MeOH
afforded diacid derivative 12. The cyclised compound 13 was prepared from
diacid derivative 12 by using acetic anhydride and sodium acetate in acetic acid,
under reflux condition, further deacylation by 6.0 N HCl in EtOH afforded keto
compound 14. Nitration of 14 was accomplished by employing nitrating mixture
(i.e. H2SO4 and HNO3) to furnish nitro compound 15. Further reduction of 15 by
NaBH4 in EtOH followed by aromatization in presence of H2SO4 in EtOH
resulted in nitro benzofuran intermediate 5 as shown in scheme−3.
Scheme−3
OH
O
O O
O
O
O
O
O
O
OH
O
OH
10 11 12
a bc
O
OAc
O
O
O
OO2N
d e
13 14 15
O
OHO2N
f O
O2N
g
16 5
Reagents and conditions: (a) methyl 2-bromohexanoate, K2CO3, ACN, reflux
16 h; (b) NaOH, MeOH, 40 °C 1h; (c) Ac2O, AcOH, NaOAc, reflux 4 h; (d) 6.0
N HCl, EtOH, reflux 4 h; (e) H2SO4, HNO3, 5 °C; (f) NaBH4, EtOH, reflux 2 h;
(g) H2SO4, EtOH, reflux, 4 h.
16
Schlama Thierry et al 15
Schlama and co-workers prepared nitro benzofuran 5 in four steps from
Salicylaldehyde (17) which was condensed with methyl 2-bromohexanoate (43)
to give ester 18. This was followed by ester hydrolysis to afford acid 19.
Nitration of acid derivative 19 followed by cyclization using acetic anhydride
furnished the desired nitro benzofuran intermediate 5 (Scheme−4).
Scheme−4
OH
O
H O
O
H
O
O
O
O
H
O
OH
17 18 19
a b
c d O
O2N
5
O
O
H
O
OH
O2N
20
Reagents and conditions: (a) methyl 2-bromohexanoate, K2CO3, DMF, 80 °C, 4
h; (b) H2SO4, HNO3, 5 °C; (c) i) 50.0% NaOH, water, 50 °C, 2h; ii) conc. HCl,
water; AcOH, NaOAc, reflux 4h; (d) Ac2O, K2CO3, 130 °C, 5h.
Several other methods were reported for the preparation of benzofuran derivatives
like condensation of 2-iodo phenol with acetylene derivatives in presence of CuI,
base and Pd/C or Pd(OAc)2,16, 17
reaction of β-keto ester with 1-bromo-2-iodo
benzene,18
cyclization of keto derivatives. 19−21
Also other methodologies were
reported through which one can synthesize required nitro benzofuran 5. 22−27
17
Kretzschmar Gerhard and co-workers 28
[Synthesis of intermediate 7]
Recently Kretzschmar Gerhard and co-workers reported the synthesis of key
intermediate 7. Acylation of phenol 21 by using valeroyl chloride gave
intermediate 22 which on cyclization in presence of tri-n-butyl amine and
molecular sieve / Fe-BEA type zeolite in xylene at reflux afforded intermediate 6.
Demethylation of 6 was carried out with dry HCl in tri-n-butyl amine
hydrochloride or using 1-butyl-4-methypyridinium tetrafluoroborate as ionic
solvent is reported as described in scheme−5.
Scheme−5
O2N
OHO
OO2N
OO
O
O
O
O
O
O2N
O
O
OH
O2N
2122
67
a
b
c
Reagents and conditions: (a) i) K2CO3, acetone, water, 40−50 °C, 1h; ii)
valeroyl chloride, acetone, -10 °C, 30 min; (b) tri-n-butyl amine, molecular sieves
or Fe-BEA type zeolite, xylene reflux, 8 h; (c) tri-n-butyl amine hydrochloride or
ionic liquid, 150 °C, 15−20 h.
The reagent and solvents involved in this process were relatively less toxic. Use
of recovered catalyst like molecular sieves at cyclization stage clearly indicated
that Kretzschmar and co-workers focused their attention on green chemistry
which was very important feature of this scheme. However requirement of high
18
temperature at cyclization and demethylation step (150 °C) was the major
concerns due to which we decided to avoid this route for commercial scale
synthesis of intermediate 7.
Shoutteeten A. and co-workers et a l 29
[preparation of intermediate 7].
Shoutteeten A. and co-workers reported preparation of key intermediate 7 by
starting from nitro compound 23. Acid catalyzed rearrangement of nitro
compound 23 using acetic acid and conc. H2SO4 at reflux was used to produce
benzofuran 24. Conversion of benzofuran 24 to corresponding acid chloride 25
by treatment with SOCl2 followed by reaction with p-anisole at 0 to 5 °C afforded
intermediate 6. Insitu demethylation of intermediate 6 was carried out using
AlCl3 at 60 °C to arrive at desired intermediate 7(Scheme−6).
Scheme−6
O
OH
O
O2N
O
O
O
O2N
6
b
c d
O
ClO
O2N
23 24
O
OHO
O2N
25
a
O
O
OH
O2N
7
Reagents and conditions: (a) AcOH, H2SO4, reflux 2 h; (b) SOCl2,
chlorobenzene, 80 °C, 9 h; (c) AlCl3, chlorobenzene, 0−5
°C, 1 h; (d) AlCl3,
chlorobenzene, 60 °C, 7 h.
19
Michel Biard and La Mure et a l 30
[FeCl3 route].
Michel Biard and La Mure reported the synthesis of Dronedarone Hydrochloride
(2) starting from nitro benzofuran 5 which on Friedel-Craft acylation with acid
chloride 29, produced intermediate 8. This reaction was carried out in DCM at 20
to 22 °C by employing FeCl3 as Lewis acid. Catalytic reduction of nitro group
was achieved by using PtO2 in EtOH followed by sulfonamide formation using
MsCl and Et3N in DCM. Hydrochloride salt formation of Dronedarone free base
was carried out in ethyl acetate using Hydrogen chloride in ether.
Main feature of this route was preparation of side chain, (Acid chloride 29)
prepared in 3 steps starting from methyl paraben (26). methyl paraben (26) was
condensed with chloro compound 42 in DMF using K2CO3 at 100 °C followed by
alkaline ester hydrolysis using 20% aqueous NaOH in MeOH under reflux. Lastly
acid chloride formation was effected for intermediate 29 with SOCl2 in
chlorobenzene (Scheme–7).
The major advantage of this route was formation of mutagenic intermediate 7 was
eliminated. Use of relatively mild and safe Lewis acid FeCl3 instead of already
reported catalysts like AlCl3 and SnCl4 for critical Friedel-Craft acylation step
was the salient feature of this route.
20
Scheme−7
OH
OO
O
OHO
N
O
ClO
N.HCl
+
O
O2N
26
28295
89
2 (free base)
e
g
d
O
O2N
O
O
N
O
O
O
NH2
N
O
O
O
NHS
O O
N
2
O
O
O
NHS
O O
N .HCl
N
Cl
+
42
a
b
c
O
OO
N
27
f
.HCl
Reagents and conditions: (a) K2CO3, DMF, 100 °C, 1 h; (b) 20.0% aq. NaOH,
MeOH, 65 °C, 2 h; (c) SOCl2, cat. DMF, chlorobenzene, 85 °C, 1 h; (d) FeCl3,
DCM, 20−22 °C, 1.5 h; (e) PtO2/H2, EtOH, RT, 20 min; (f) MsCl, Et3N, DCM,
RT, 20 h; (g) HCl−ether, ethyl acetate, 45 min.
21
Fino, N and co-workers et a l 13
[sulfonamide route].
Fino and co-workers started their synthesis from conversion of nitro benzofuran
derivative 5 (Scheme–8) into respective sulfonamid intermediate 31 by first
reducing nitro group using PtO2/ H2 or Pd/C and ammonium formate to obtain
respective amino benzofuran 30. Which was then treated with MsCl in mixture of
THF and MTBE using aq. ammonia to afford sulfonamide 31. Acid chloride 29
was then coupled with sulfonamide 31 using FeCl3 to afford Dronedarone free
base which was further converted in Dronedarone Hydrochloride (2) using conc.
HCl in IPA.
Scheme−8
O
ClO
N.HCl
O
O2N
29
5
2 (free base)
e
O
NH2
30
O
NHS
O O +
a or b c
d
31
O
O
O
NHS
O O
N
2
O
O
O
NHS
O O
N .HCl
Reagents and conditions: (a) PtO2/H2, EtOH, 20–50 °C; (b) Pd/C, HCOONH4,
EtOH, 50 °C, 5 h; (c) MsCl, aq. NH3, THF, MTBE, 20 °C; (d) FeCl3, DCM,
20−22 °C, 2 h; (e) conc. HCl, IPA.
22
Monahnarangam S. and co-workers et a l 31
Monahnarangam S. and co-workers reported synthesis of intermediate 7 from
nitro benzofuran 5 with little modification i.e. they had used AlCl3 for
Friedel−Craft acylation instead of reported SnCl4. Further O-alkylation of
intermediate 7 was performed by using 1-Bromo-3-chloropropane and K2CO3 in
DMF to provide chloro derivative 32.
Transfer hydrogenation (Pd/C and HCOONH4) was employed for nitro to amine
functional group transformation which resulted in compound 33 as described in
scheme−9.
Scheme−9
O
O2N
O
O2N
O
O
5
a b
c
O
O2N
O
OH
d
6 7
O
O2N
O
OCl
O
O
OCl
NH2
32 33
Reagents and conditions: (a) p-anisoyl chloride, AlCl3, DCM, 25 °C, 4 h; (b)
AlCl3, chlorobenzene, 85 °C, 4 h; (c)1-bromo-3-chloropropane, K2CO3, DMF, 25
°C, 20 h; (d) Pd/C, HCOONH4, IPA, 50 °C, 30 min.
Sulfonamide formation was carried out in biphasic mixture of water and DCM
using MsCl and NaHCO3 as base. Lastly coupling of di-n-butylamine with
sulfonamide 34 followed by hydrochloride salt formation by ethyl acetate−HCl
provided Dronedarone Hydrochloride (2) as disclosed in scheme−10.
23
Scheme−10
a b
c
.HCl
2
O
O
O
NHS
O O
N
O
O
O
NHS
O O
N
O
O
OCl
NH2
O
O
O
NHS
O O
Cl
33 34
2 (free base)
Reagents and conditions: (a) MsCl, NaHCO3, DCM, 35 °C, 6 h; (b) di-n-butyl
amine, DMF, 125 °C, 4 h; (c) EtOAc-HCl, EtOAc, 25 °C, 2 h.
Sada M. and co-workers et a l 32
[Dimesyl route]
Sada, M. and co-workers successfully completed synthesis of Dronedarone
Hydrochloride in four steps starting from readily available intermediate 7.
Coupling of intermediate 7 with 3-chloro-1-propanol in presence of TBAB, KI,
and base K2CO3 in DMF yielded compound 35. Catalytic reduction of compound
35 into amino derivative 36 was accomplished by Pd/C and H2. Dimesyl
intermediate 37 was synthesised by using MsCl and pyridine in DCM, 37 on
treatment with di-n-butyl amine gave Dronedarone free base which was
subsequently converted into Dronedarone Hydrochloride (2) as depicted
scheme−11.
24
Scheme−11
O
O2N
O
OH
O
O2N
O
OOH
O
O
O
NH2
OH
O
O
O
NHS
O O
OMs
a bc
7 35 36
37
de
2 (free base) 2
O
O
O
NHS
O O
N
O
O
O
NHS
O O
N
Reagents and conditions: (a) 3-chloro-1-propanol, K2CO3, KI, TBAB, DMF, 85
°C, 5 h; (b) Pd/C, H2 MeOH, 40 °C; (c) MsCl, pyridine, DCM, RT, 24 h; (d) di-n-
butyl amine, ACN, reflux 5 h;(e) conc. HCl. acetone.
Arie Gutman and co-workers et a l 33
[p-Anisidine route]
Arie Gutman and co-workers reported synthesis of Dronedarone Hydrochloride
(2) in three stages i.e. synthesis of sulfonamide 31, preparation of acid chloride 29
and coupling of these intermediates to afford 2.
Inexpensive p-anisidine (38) was used in the synthesis of sulfonamide 31. Acetic
anhydride was employed for N-acetyl protection of p-anisidine (38) to afford
acetamide compound 39, Friedel-Craft acylation of acetamide 39 with 2-
bromohexanoyl chloride along with insitu demethylation resulted in bromo
intermediate 40 as presented in Scheme−12.
25
Scheme−12
O
NH2
O
NH
O
OH
NH
O
Br
O
3839 40
O
NH2
30
HCl.
O
NHS
O O
31
a b c
d
Reagents and conditions: (a) Ac2O, DCM, hexane, 25−30 °C, 1 h; (b) 2-bromo
hexanoyl chloride, AlCl3, DCM-CH3NO2, RT, overnight; (c) i) NaHCO3, MeOH,
reflux 2 h; ii) NaBH4, MeOH, 0−5 °C; iii) dil. HCl, MeOH, reflux, 5 h; (d) MsCl,
toluene, reflux, 2 h.
Preparation of amino benzofuran 30 from bromo compound 40 was
accomplished in four steps following a sequence of chemical transformations like
cyclization (using NaHCO3), reduction of carbonyl group (by NaBH4),
aromatization and deprotection (both steps were acid catalyzed). Free base of
amino benzofuran 30 on treatment with MsCl in toluene, at reflux condition,
furnished sulfonamide 31.
Preparation of acid chloride 29 started with O-alkylation of methyl paraben (26)
with 1,3-dibromo propane at reflux condition in MEK by using K2CO3 as base.
Condensation of bromo ester 41 with di-n-butyl amine gave intermediate 27
followed by acid catalysed ester hydrolysis to afford acid 28. Conversion of acid
28 to the corresponding acid chloride 29 was accomplished with SOCl2 in DCM
(Scheme−13).
26
Scheme−13
OO
OH
OO
O Br
OO
O N
OHO
O N
ClO
O N
a b
c d
26 27
.HCl .HCl
2829
41
Reagents and conditions: (a) 1,3-dibromo propane, K2CO3, MEK, reflux 6 h;
(b) di-n-butyl amine, toluene, reflux, 3 h; (c) conc. HCl, reflux 5 h; (d) SOCl2,
DCM, reflux, 1 h.
Dronedarone free base was prepared by drop wise addition of SnCl4 into the
mixture of acid chloride 29 and sulfonamide 31 in DCM at 0−5 °C to provide
crude Dronedarone free base. This crude free base was further purified by column
chromatography and treated with hydrogen chloride 10% solution in ethyl acetate
to obtain Dronedarone Hydrochloride (2) as per scheme−14.
27
Scheme−14
O
NHS
O O +
ClO
O N.HCl
O
NHS
O O
ON
O
O
NHS
O O
ON
O
.HCl
31 29
2 (free base) 2
a
b
Reagents and conditions: (a) SnCl4, DCM, 25 °C, 2 h; (b) HCl 10% sol
n in
EtOAc, EtOAc, 0−5 °C, 1 h.
Condensation of sulfonamide 31 and acid chloride 29 was low yielding reaction
and accompanied with high impurity formation, hence required chromatographic
purification due to which this process was not commercially viable.
Present Work
28
Present work
The retro synthetic analysis depicted in scheme−15 suggested that Dronedarone
(2) can be assembled from the two critical fragments namely benzofuran
derivative 46 and the acid 47. Benzofuran derivative 46 and the acid 47 can be
condensed which would give the coupled product 45. Intermediate 45 inturn
could be converted to the immediate precursor 44 of Dronedarone by replacing
−Cl group of 45 with dibutyl amine.
Scheme−15
O
O
ON
NHS
O OO
O
ON
NHProt
O
O
OCl
NHProt
O
NHProt
+
OHO
O Cl
244
45
4647
Finally, the protection group on intermediate 44 can be removed and sulfonamide
formation can be effected to arrive at the target compound (2).
The acid fragment 47 could be obtained from very common and economically
available raw material 4-hydroxymethyl benzoate (26), which is also known as
methyl paraben as shown in scheme−16.
29
Scheme−16
OHO
O Cl
OO
O Cl
OO
OH
48 4726
The synthesis of benzofuran moiety 46 could be achieved from commercially
available and inexpensive raw material p-anisidine (38) by following literature
procedure33
with obligatory changes as shown in scheme−17.
Scheme−17
OH
NH
O
Br
O
40
O
NH2
O
NH2
3830
O
NHProt
46
p-anisidine (38) can be converted to the benzofuran 30 via bromo intermediate 40
and finally can be shielded with suitable protecting group.
With this intention, we started our synthetic campaign towards the benzofuran
derivative 30 using p-anisidine (38) as the starting material. Accordingly, N-
acetylation of p-anisidine (38) was achieved by using acetyl chloride as
acetylating reagent instead of reported acetic anhydride as shown in scheme−18.
Scheme−18
O
NH2
O
NH
O
38 39
i) CH3COCl/ NaOH
ii) acetone/ water
90%
30
During the optimization of reaction conditions for the synthesis of acetamide 39,
various solvents like DCM, EtOAc, THF, DMF, toluene, acetone and
acetone−water mixture were examined. Combination of acetone−water (1:4) was
found to be the best media because the compound 39 was insoluble in this solvent
system. Hence, after completion of reaction, isolation of pure product was
achieved by simple filtration followed by water wash without any additional work
up. Structure of 39 was confirmed by 1H NMR and mass [m/z: 166.0 (M+H)
+]
spectrum.
Condensation of 2-bromo hexanoyl chloride by Friedel-Craft acylation with insitu
demethylation using AlCl3 as Lewis acid provided the formation of bromo
compound 40. As use of AlCl3 was beneficial due to insitu demethylation no
other Lewis acids were tried for this conversion (Scheme−19).
Scheme−19
O
NH
O
OH
NH
O
Br
O
3940
2- bromo hexanoyl chloride
AlCl3 DCM-nitromethane
82%
Conversion of bromo compound 40 into desired amino benzofuran hydrochloride
30 was carried out in three insitu chemical transformations. Initially bromo
compound 40 was refluxed with NaHCO3 in methanol to obtain cyclic keto
compound 49, followed by reduction of carbonyl group was achieved by using
NaBH4 to obtain hydroxyl compound 50 as shown in scheme−20.
31
Scheme−20
OH
NH
O
Br
O
NH
O
O
O
40 49
NH
O
OH
O
NH2
O
HCl.
30
NaHCO3 MeOH NaBH4
dil. HCl
75%
50
Finally, dehydration and deprotection were completed by using dil. HCl in single
step to afford essential amino benzofuran hydrochloride 30 as described in
scheme−20. Presence of signal for one proton as singlet at 6.69 ppm in 1H NMR
and mass spectrum [m/z: 190.0 (M+H)+] confirmed the structure of amino
benzofuran 30.
After successful synthesis of key intermediate 30, we focused our attention on the
other fragment 47 required for the preparation of Dronedarone Hydrochloride. As
shown in the retro scheme−16 for arriving at the acid intermediate 47, we decided
to use methyl paraben (26) as starting material. Initially, we tried alkylation of
methyl paraben (26) with 1,3-dibromo propane as per literature condition,33
unfortunately the outcome of this reaction was not satisfactory as formation of
considerable amount of dimeric biproduct (51) was observed along with desired
alkylated product 41 (Scheme−21).
Scheme−21
OO
OH
+ Br Br
OO
O Br
+
O O
OO OO
K2CO3/DMF
26 1,3-Dibromo propane 41 51
32
In order to minimize the dimeric impurity formation, we decided to use 1-bromo-
3-chloro propane (BCP) instead of 1,3-Dibromo propane for alkylation reaction.
Accordingly, methyl paraben (26) was treated with BCP using K2CO3 as base and
various solvent systems such as THF, acetone, DMF, MIBK and under heating
condition heating condition using BCP as alkylating reagent and solvent. Best
result was observed by addition of catalytic amount of DMF in to the reaction
mixture under neat condition during which formation of dimeric impurity 51 was
minimized. After work up and simple purification from cyclohexane the desired
alkylated product 48 was isolated in more than 90% with high purity
(Scheme−22).
Scheme−22
OO
OH
OO
O Cl
OHO
O Cl
ClO
O Cl
26 48 47 52
BCP
K2CO3/DMF
88% 88%
NaOH/HCl
MeOHSOCl2/DCM
After several experiments we were able to optimize the quantity of BCP to be
used in reaction up to 3.2 eq. which was finalized for scale up batch. Structure of
chloro compound 48 was confirmed by 1H NMR. In
1H NMR spectrum, protons
of –CH2Cl, and –OCH2 group resonated at 3.75 ppm (t, 2H) and 4.17 ppm (t, 2H)
respectively.
Saponification of methyl ester of chloro compound 48 was achieved with NaOH
in MeOH−water. During this hydrolysis step methoxy impurity was observed in
the range of 2−5% along with desired acid 47. At this stage we felt that
presence/contamination of this impurity 53 in the acid 47 is not going to pose the
problem as this impurity is not going to involve in the amination step so could be
easily removed during the salt the formation at later stage of synthesis
(Scheme−23).
33
Scheme−23
OO
O Cl
OHO
O Cl
+
O O
OHO
48 47 53 (2-5%)
NaOH
MeOH/water
Using our optimized conditions we could achieve 88% yield of the required acid
fragment (47) having around 2% of impurity 53 and decided to proceed further
(without trying further purification).
Once we had both the fragments amino benzofuran hydrochloride 30 and acid 47
(or acid chloride 52), the next thing left was the coupling of amino benzofuran
hydrochloride 30 with acid 47 as shown in scheme−24.
Scheme−24
O
NH2
+
OHO
O Cl
O
NH2
O
OCl
F-C acylation
30 47 54
Prior to trying any Friedel-Craft reaction of 30 and 47 we felt that the protection
of amino group of benzofuran 30 could interfere in the Friedel-Craft reaction and
would result in amide formation. With this intention, we decided to protect the
amine group of benzofuran 30 before the Friedel-Craft reaction.
Literature survey on Dronedarone33
indicated that use of the desired sulfonamide
derivative 31 was blocked. Also use of several other protecting group like amide
34
and carbamates was restricted hence, we decided to evaluate the utility of
phthalimido group for protection of aminobenzofuran 30. This approach is
advantageous because,
phthalimido protection is stable for wide verity of reaction conditions.34, 35
The required reagent phthalic anhydride is inexpensive and available at
bulk scale.
Deprotection of phthalimido group can be achieved under very mild
conditions using aqueous solution of monomethyl amine or hydrazine
hydrate.36
Accordingly, hydrochloride salt of amino benzofuran 30 was treated with aqueous
NaHCO3 and free base 30 was extracted in toluene. Further this solution of 30 in
toluene, phthalic anhydride and catalytic Et3N were added and reaction mass was
refluxed for 1.5 h with azeotropic distillation of water (Scheme−25).
Scheme−25
O
NH2
O
N
O
O
30 55
Phthalic anhydride
Et3N/toluene
93%
After completion of reaction, reaction mass was diluted with cyclohexane product
was isolated by filtration in excellent yield (93%). In 1H NMR presence of
additional signals for four protons in aromatic region at 7.76−7.80 ppm (2H) and
7.93−7.97 ppm (2H) confirmed the structure of phthalimido derivative 55. As
we got excellent yield and purity, further optimization was not required.
Friedel−Craft acylation of phthalimido compound 55 with acid 47 or acid chloride
52 was the most critical reaction of our synthetic scheme and hence, we decided
to make this transformation more efficient (less impurity formation) high yielding
and simpler with respect to Lewis acid catalysts generally used for the
Friedel−Craft reaction (Scheme−26).
35
Scheme−26
O
N
O
O
+
XO
O Cl
O
N
O
O
O
OCl
Lewis acid
55 47 or 52 56
where, X = -OH or -Cl
Accordingly, we intended to examine various Lewis acid systems for catalysing
the critical conversion; the results of our efforts are summarized in table−1.
Table−1
Sr. No. −X Lewis acid Condition Result Ref
1 -Cl AlCl3 DCM, -20 °C, 1h 68%
a 37
2 -Cl FeCl3 DCM, reflux, 6 h NA 37
3 -OH ZnCl2−Al2O3 DCM, reflux, 5 h NA 38
4 -Cl SnCl4 DCM, 0 to 25 °C, 1h 80%
a 37
5 -Cl ZnO DCM, 25 °C, 24 h NA 39
6 -OH P2O5−Al2O3 EDC, reflux, 24 h NA 40
7 -OH P2O5−SiO2 EDC, reflux, 24 h NA 41
8 -Cl Zn(OTf)2.6H2O CH3NO2, 25
°C, 24 h NA 42
a
Isolated yields.
Even though variety of Lewis acids were examined, only AlCl3 and SnCl4 were
found to be effective. Best results were obtained by using 3.0 eq. of SnCl4
(table−1, Entry−4) for Friedel-Craft acylation from which chloro compound 56
was obtained in 80% yield. Structure of chloro compound 56 was confirmed by
1H NMR. The disappearance of singlet at 6.69 ppm due to benzofuran and
appearance of additional peaks due to the other fragment in 1H NMR spectrum
confirmed the structure of compound 56.
36
Chloro compound 56 was further converted to desired Dronedarone
Hydrochloride (2) successfully as shown in scheme−27.
Scheme−27
2
O
N
O
O
O
OCl
56
O
NH
O
ON
SO O
.HCl
Even though the final product was completely devoid of any metal contamination
(tin content was below detection limit in API) and overall yield and purity of
Dronedarone Hydrochloride (2) was good, because of the risk involved in
industrial scale handling of SnCl4 and the resulting large quantity of toxic tin
waste, we intended to eliminate the use of SnCl4 in our commercial
manufacturing process of Dronedarone Hydrochloride (2).
With this intention we decided to focus on non-metallic catalyst for the
Friedel−Craft acylation. During our search we came across a report 43
in which
use of poly phosphoric acid (PPA) and P2O5 for affecting this transformation was
discussed. When we tried the same conditions for the condensation of
phthalimido compound 55 with acid derivative 47, the desired product chloro
compound 56 was isolated in good yield. Encouraged by these results, we looked
for better condition which can be used on commercial scale.
Eaton‟s reagent (1:10 P2O5 in MSA) discovered by P. E. Eaton in 1973 could to
be a good alternative to PPA or PPA−P2O5 as it overcomes the critical drawbacks
of PPA due to its lower viscosity, easy handling and product isolation does not
require any special complex separation procedures.44
Many synthetic schemes45–48
involving Eaton‟s reagent are not only more
economical but also more environment friendly and offer a number of distinct
advantages such as,
37
Safety on industrial scale.
Avoids additional medium required because the raw materials often
dissolve in the reagent rapidly.49
High-purity products with excellent yields.
The distinctive physical and chemical properties of Eaton‟s reagent makes it a
very useful reagent in many reactions with different applications.44−57
Several uses of Eaton‟s reagent from the literature have been described in the next
few schemes to demonstrate the ability of Eaton‟s reagent to accomplish these
kinds of transformations.
Scheme−28
NHOMe
OMe
O
O
OMe
Eaton's reagent
OMe
NH
O
O
OMe
Zewge described a high-yielding methodology for the cycloacylation of aniline
derivatives to 4-quinolones in the presence of Eaton's reagent (Scheme−28).51
Scheme−29
OH
OHOH
+
O
OH
OH O
OH
OH
O
Eaton's reagent
Preparation of biologically active Xanthones derivatives (novel anti-HIV agent)
using Eaton‟s reagent was published by Shi, Lee and co-workers. 52
(Scheme−29)
38
Scheme−30
Eaton's reagent
N
O
I
NH
EtO O
O
OEt
NH
OEt
O O
I
N
O
Dorow and Co-workers developed a route for the synthesise of Pyrrolquinolone
PHA-529311 in which cyclization was accomplished by using Eaton‟s reagent as
depicted in scheme−30.
Scheme−31
NH2
+O
O
O
Oref - 55 N
HO
OH
Im and his colleagues prepared 4-hydroxy quinolinone, an important hetrocyclic
member from aniline in excellent yield by using Eaton‟s reagent.55
(Scheme−31).
Scheme−32
Cl
O
NH
(CH2O)n, Eaton's
ref - 48 N
O
Cl
Yang and his colleagues reported a scalable approach for the cyclization of
substituted phenylacetamide analogues to tetrahydroisoquinoline-2-one utilizing
Eaton‟s reagent48
(Scheme−32).
From the preceding lines it is clearly evident that, Eaton‟s reagent could be an
excellent alternative to the most recent condition (PPA−P2O5) worked for us,
hence we decided to try this reagent for our transformation. Prior to its use in our
scheme we thought to check its utility for the Friedel−Craft reaction involving the
known fragments sulfonamide 31 and acid derivative 28, the results could give us
39
an idea about its performance in comparison with reported conditions for the same
fragments. Consequently we carried out condensation of sulfonamide 31 with
acid derivative 28 by using Eaton‟s reagent and we got desired Dronedarone
Hydrochloride (2) with good yield and purity.
Accordingly, commercial Eaton‟s reagent (5 volumes, 7.7% Solution) was used
for the coupling of phthalimido compound 55 with acid 47 and we were pleased
to see a much better reaction profile when compared to all other conditions
including PPA−P2O5 and the isolated yield of the desired product was 75%.
According to Eaton,44
methanesulfonic anhydride is formed in this mixture while
other species are also present, such as PPA and mixed anhydride of PPA and
MSA.49
Hence it is clear that completion of reaction is dependent on mole
equivalents of P2O5 (which gives methanesulfonic anhydride and mixed
anhydride) and not on volumes of Eaton‟s reagent. By considering this fact, in
an attempt to reduce the volumes and to increase the efficiency of reaction, we
conducted several experiments, in which volume of MSA was not changed and
only the quantity of P2O5 was altered. From all our efforts, we concluded that 2.5
mol. Eq. of P2O5 is optimum quantity to get best results with respect to yield and
reaction time, the results are summarized in Table−2.
Table−2
Sr. No Mol .eq. of P2O5 time Result
1 0.33 36 h In complete reaction
2 0.5 36 h In complete reaction
3 1.0 24 h 70%
4 1.5 12 h 72%
5 2.0 4 h 73%
6 2.5 1 h 75%
7 3.0 50 min 75%
8 4.0 50 min 72%
40
After successfully finding a better, non-hazardous, non-metallic, commercially
available reagent and an optimized condition for the critical Friedel-Craft
acylation, we could generate enough quantity of the intermediate 56. Now the,
only thing left for us was the transformation of chloro derivative 56 to final
Dronedarone Hydrochloride (2) which was planned following a series of simple
transformations as shown in scheme−33.
Scheme−33
O
N
O
O
O
OCl
O
N
O
O
O
ON
O
NH2
O
ON
O
O
ON
NHS
O O
.HCl
5657
582
The first thing to be taken care of was the displacement of –Cl group of
compound 56 with the desired di-n-butyl amine. When this amination was tried,
we found out the conversion to be sluggish as the reaction took almost 72 h at 100
°C using 2 eq. of di-n-butyl amine in DMF. Hence the reaction condition was
optimized and we found that addition of 1 eq. of KI and catalytic amount of PTC
(TBAB or TBAI) accelerated the rate of reaction dramatically and the reaction
was completed in 6 h. Further, various solvents like toluene, MEK, MIBK,
acetone and DMF were tried and out of all these solvents, we found that DMF
was most appropriate solvent for this conversion. After all these experiments,
41
amination of chloro derivative 56 using di-n-butyl amine under the optimized
conditions was successfully furnished amino derivative 57 in excellent yield.
During process development amine compound 57 was isolated as its
hydrochloride salt, but later on we decided to use the free base (viscous oil) as it
is and proceeded for the next step (Scheme−34).
Scheme−34
O
N
O
O
O
OCl
O
N
O
O
O
ON
56 57
Di-n-butyl amine
TBAB, KI, DMF
Deprotection of Phthalimido group has been reported using various reagents like
hydrazine hydrate, mono methyl amine, NaBH4−AcOH, out of which commercial
monomethyl amine 40% aq. solution was one of the most economical reagent,
and hence was selected as the reagent of choice for our deprotection. During
process development this reagent worked very well in first stroke, and after
completion of reaction amine 58 was isolated as oil. Hence, other conditions
were not examined.
As per the regulatory requirement, for any API process the precursor of API
should have maximum possible purity and should fulfil QA requirements. So it
was necessary to develop a purification method for this particular intermediate
58. But as amino compound 58 was oil, it was very difficult to develop a
convenient purification method. At initial stage column chromatography was
employed for the purification of the free base 58, but as use of column
chromatography for purification is exorbitant technique for commercial synthesis,
we decided not to adopt this technique for purification and find out the better
alternative. Also, another issue associated with use of the free base 58 was the
observed colour change of purified free base (oil) from pale yellow to the light
42
brown during the holding time study, which raised some doubt about stability of
compound.
Hence, we decided to eliminate these issues at such an advanced stage which
could later prove crucial and jeopardize our process. We thought, suitable salt
formation of amino compound 58 was the easiest and immediate solution to these
problems. Accordingly we examined various organic acids like citric acid,
fumaric acid, benzoic acid, salicylic acid, oxalic acid, acetic acid, tartaric acid,
methanesulfonic acid and mineral acids like HCl, HBr, H2SO4 and HNO3 for the
salt formation process. Out of all these acids, only oxalic acid worked well and
we could isolate the corresponding dioxalate salt as crystalline solid while in all
other cases, either sticky mass or no crystallization of the salt was observed.
Isolation of amino compound 58 as dioxalate salt resolved the complications in
purification. Efficient recrystallization of the dioxalate salt of 58 was achieved
from methanol to afford a purity of >99%. Holding time study of dioxalate salt of
58 was performed and found that of the salt was stable at ambient condition for at
least one month. Finalised reagents and conditions are summarized in
scheme−35.
Scheme−35
O
N
O
O
O
ON
O
NH2
O
ON
57free base 58
Mono methyl amine
Oxalic acid
IPA
O
NH2
O
ON
.2COOH
COOH
58
MeOH
43
The only thing left to complete our synthesis was the sulfonamide formation of
the amino group of 58. The major concern in this step was the formation of
disulfonamide impurity 59, which was well documented.59, 60
As per ICH guide
lines, the limit for known impurity like 59 is 0.15% and hence it was essential to
control its formation during reaction itself. In this direction before initiating work
for this step, we synthesised and isolated this impurity using excess
methanesulfonyl chloride (2.5 equiv) and DIPEA as base in DCM which is
described in scheme−36.
Scheme−36
O
NH2
O
ON
.2COOH
COOH
O
O
ON
NHS
O O
582 (minor)
O
O
ON
NS
O O
S
O
O
+
58 (major)
MsCl
DIPEA
DCM
In 1H NMR spectrum a singlet integrating for 6H was observed at 3.35 ppm and
mass [ (M+H)+
= 635.0] confirmed the structure of disulfonamide impurity.
In an effort to arise at the best conditions for the mesylation reaction, various
solvents such as DCM, chloroform, THF, toluene, ethyl acetate and acetone were
screened and it was observed that in chlorinated solvents like DCM and
chloroform, disulfonamide impurity 59 formation started from the beginning of
the reaction, while in case of other solvents like THF, ethyl acetate and acetone, it
started forming after major product formation. However, in toluene reasonably
less impurity formation with completion of reaction was observed. Thus toluene
was found to be the suitable solvent for this conversion.
After solvent selection, further fine tuning of the process was required. Organic
bases such as DIPEA, Et3N, pyridine and N-methyl morpholine were screened at
44
various temperatures between -5 to 50 °C to find out the best condition for
minimal disulfonamide formation (Scheme−37).
Scheme−37
O
NH2
O
ON
.2COOH
COOH
O
O
ON
NHS
O O
.HCl
58
2
MsCl/Et3N
toluene
55%
O
O
ON
NHS
O O
free base 2
dil. HCl/DCM
From all our efforts, we concluded that adding 1.05 equiv. of MsCl dropwise in
presence of Et3N in toluene at -5 to 5 °C gives the best results with high yield of
Dronedarone free base and negligible impurity formation (59). We wanted to
take advantage of the fact that Dronedarone hydrochloride is soluble in
chlorinated solvents like DCM, CHCl3 and decided to affect the salt formation
using dilute HCl. Accordingly Dronedarone free base in DCM was treated with
dilute HCl and the resulting salt was extracted in to DCM. Removal of solvent
and treating the crude mass (viscous oil) with EtOAc:IPA (9:1) provided
Dronedarone Hydrochloride as filterable solid. At this stage purity of API was
99% having 0.5% impurity 59, and hence further purification was needed to
comply the ICH norms. This problem was resolved by single recrystallization of
99% pure Dronedarone Hydrochloride from acetone, which afforded Dronedarone
Hydrochloride (2) with purity more than 99.5% and any individual impurity less
than 0.1%.
45
Conclusion
In conclusion we have, developed a industrially feasible, commercial process for
the manufacturing of antiarrhythmic drug Dronedarone Hydrochloride (2) as
shown in scheme.
Scheme
O
N
O
O
O
OCl
O
N
O
O
O
ON
O
NH2
O
ON
.2COOH
COOH
O
O
ON
NHS
O O
.HCl
5657
58
2
i) Di-n-butyl amine
70%
ii) TBAB, KI
iii) DMF
i) Mono methyl amine
ii) Oxalic acid/ MeOH
i) MsCl/Et3N
ii) dil. HCl/DCM
55%
O
NH2HCl.
O
N
O
O
30
55
i) Phthalic anhydride
ii) Et3N/toluene
93%
+
COOH
OCl
47
Eaton's reagent
75%
Our process has several distinct advantages over reported routes:
46
The API was synthesised in good overall yield with very high HPLC
purity, and complies the ICH guidelines.
Critical n-1 intermediate (amino derivative 58) was isolated in its purest
and stable form as dioxalate salt.
Best condition for final mesylation reaction under which minimal
formation of disulfonamide 59 was achieved.
Elimination of Hazardous/Toxic metal catalyst (Lewis acids) for the
critical Friedel-Craft acylation reaction was accomplished.
Utility of simple and commercial Eaton‟s reagent was demonstrated in
critical Friedel-Craft acylation step successfully.
Experimental
47
Experimental
Preparation of N-(4-methoxyphenyl)acetamide (39).
O
NH
O
To the stirred suspension of p-anisidine (100.0 g, 0.812 mol) in acetone (50.0
mL), NaOH (98.0 g, 1.225 mol) dissolved in D. M. water (400.0 mL), was
charged at 5 to 10 °C. Acetyl chloride (96.0 g, 1.223 mol) was charged drop
wisely controlling exotherm up to 25 °C. After complete addition of acetyl
chloride suspension was stirred for additional 2 h at 25 to 30 °C and product was
filtered followed by water wash (100.0 mL x 3) and lastly washing with
cyclohexane (100.0 mL x 2). Wet cake was dried at 50 °C to get acetamide
intermediate 39 (121.0 g, 90%).
mp: 127−128 °C; m/z: 166.0 (M+H)
+ ;
1H NMR (400 MHz, CDCl3): δ 2.12 (s,
3H), 3.77 (s, 3H), 6.82 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.56 (brs,
1H); 13
C NMR (100 MHz, CDCl3): 24.0, 55.3, 113.8, 122.0, 131.0, 156.2, 168.7.
Preparation of N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide (40).
OH
NH
O
O
Br
To the stirred solution of acetamide 39 (100.0 g, 0.605 mol) in DCM (250.0 mL)
charged AlCl3 (242.5 g, 1.819 mol) portion wise under inert atmosphere by
controlling exotherm up to 25 °C followed by subsequent addition of nitro
48
methane (113.5 g, 1.859 mol) and 2-bromohexanoyl chloride (155.0 g, 0.726 mol)
at 5 to 10 °C. After stirring the reaction at ambient temperature for 4 h, second lot
of AlCl3 (80.7 g, 0.605 mol) was charged and reaction mass was stirred at
ambient temperature for overnight. Reaction was quenched by careful addition of
reaction mass over ice-cold water followed by distillation of solvents. After
complete distillation of DCM resulting suspension was filtered and solids were
washed with D.M. water (100.0 mL x 2) followed by toluene wash (100.0 mL).
Wet cake was dried at 50 °C to get bromo compound 40 (164.0 g, 82%).
mp: 136−138 °C; m/z: 328.1 (M+H)
+ ;
1H NMR (400 MHz, CDCl3): δ 0.92 (t, J =
7.0 Hz, 3H), 1.34−1.49 (m, 4H), 2.09−2.17 (m, 2H), 2.19 (s, 3H), 5.14 (t, J = 7.0
Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 7.21 (s, 1H), 7.42 (dd, J = 8.9 Hz, J = 2.3 Hz
1H), 8.19 (d, J = 2.3 Hz, 1H), 11.82 (s, 1H); 13
C NMR (100 MHz, CDCl3): 13.8,
22.2, 24.1, 29.4, 32.8, 46.4, 116.4, 119.0, 121.3, 129.3, 129.9, 160.0, 168.7, 198.6.
Preparation of 2-butyl-5-aminobenzofuran hydrochloride (30).
O
NH2HCl.
Bromo compound 40 (100.0 g, 0.305 mol) was added portion wise to the
suspension of NaHCO3 (51.2 g, 0.610 mol) in MeOH (500.0 mL). The
suspension was refluxed for 2 h. Reaction mass was cooled at 5 °C and charged
solution NaBH4 (4.7 g, 0.123 mol) dissolved in 1% NaOH solution (15.0 mL)
drop wisely over a period of 1 h. After stirring for 2 h at 5 °C reaction mass was
acidified by adding 6.0 N HCl solution (750.0 mL) followed by stirring at 80 °C
for 6 h. After completion of hydrolysis, suspension was chilled at 10 °C and
filtered after 2 h. Washing of wet cake with chilled ethyl acetate (50.0 mL x 2)
followed by drying obtains amino benzofuran hydrochloride 30 with good yield
(51.5 g, 75%).
mp: 190−193 °C; m/z: 190.0 (M+H)
+ ;
1H NMR (400 MHz, DMSO_d6): δ 0.90 (t,
J = 7.4 Hz, 3H), 1.30−1.39 (m, 2H), 1.62−1.69 (m, 2H), 2.77 (t, J = 7.4 Hz, 2H),
49
6.69 (s, 1H), 7.23 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 7.57−7.61 (m, 2H), 10.45 (brs,
3H); 13
C NMR (100 MHz, DMSO_d6): 13.9, 21.9, 27.6, 29.4, 102.6, 111.9,
115.4, 118.6, 126.1, 129.8, 153.4, 162.0.
Preparation of 2-(2-butyl-1-benzofuran-5-yl)-1H-isoindole-1,3(2H)dione
(55).
O
N
O
O
Amino benzofuran hydrochloride 30 (100.0 g, 0.443 mol) was slowly added to a
stirred mixture of NaHCO3 (50.0 g, 0.595 mol), water (300.0 mL) and toluene
(150.0 mL) by controlling frothing. After 30 min, layers were separated and the
organic layer was washed with water (100.0 mL). Phthalic anhydride (66.0 g,
0.445 mol) and Et3N (4.5 g, 0.044 mol) was sequentially added to the organic
layer containing the free amine and the reaction mass was refluxed for 1.5 h with
azeotropeic removal of water. The reaction mixture was allowed to cool at 75 °C
where upon cyclohexane (300.0 mL) was added and the mixture was cool down to
20 °C and stirred for 1 h. The precipitated solids were filtered, washed with
cyclohexane (100.0 mL) and dried at 50 °C to afford phthalimido compound 55
(132.0 g, 93%).
mp: 150 −152 °C; m/z: 320.1 (M+H)+
; 1H NMR (400 MHz, CDCl3): δ 0.96 (t, J =
7.4 Hz, 3H), 1.38−1.47 (m, 2H), 1.70−1.78 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H), 6.42
(s, 1H), 7.20 (dd, J = 8.6 Hz, J = 2.2 Hz, 1H), 7.49−7.52 (m, 2H), 7.76−7.80 (m,
2H), 7.93−7.97 (m, 2H); 13
C NMR (100 MHz, CDCl3): 13.6, 22.1, 28.0, 29.6,
102.0, 111.1, 118.9, 121.8, 123.5, 126.0, 129.6, 131.7, 134.1, 153.8, 161.1, 167.6.
50
Preparation of methyl 4-(3-chloropropoxy)benzoate (48).
OO
O Cl
Sodium methylparaben (26) (100.0 g, 0.574 mol) and powdered K2CO3 (40.0 g,
0.289 mol) were mixed with solution of 1-Bromo-3-chloro propane (BCP) (290.0
g, 1.842 mol), DMF (10.0 mL) and heated at 90 °C for 6 h. After completion of
reaction above suspension was cooled and quenched with D. M. water (200.0
mL), layers were separated and organic layer was washed with D. M. water
(200.0 mL). Excess of 1-bromo-3-chloro propane was distilled out completely
under reduced pressure and resultant residue was diluted with cyclohexane (200.0
mL) followed by cooling of the reaction mass to 0−5 °C was done to crystallized
the product. The precipitated solids were filtered, washed with chilled
cyclohexane (50.0 mL x 2) and dried under vacuum at ambient temperature to
give chloro compound 48 as low melting solid (120.0 g, 91%).
mp: 58−60 °C; m/z: 228.8 (M+H)+
; 1H NMR (400 MHz, CDCl3): δ 2.22−2.28
(m, 2H), 3.75 (t, J = 6.3 Hz, 2H), 3.88 (s, 3H), 4.17 (t, J = 5.8 Hz, 2H), 6.91 (d, J
= 14.5 Hz, 2H), 7.98 (d, J = 14.5 Hz, 2H); 13
C NMR (100 MHz, CDCl3): 31.8,
41.1, 51.6, 64.2, 113.8, 122.5, 131.4, 162.2, 166.5.
Preparation of 4-(3-chloropropoxy)benzoic acid (47).
O Cl
OHO
Chloro compound 48 (100.0 g, 0.437 mol) was added to a mixture of MeOH
(400.0 mL) and 20.0% w/v aq. NaOH solution (100.0 mL) and refluxed for 2 h.
51
After completion of saponification, reaction mass was diluted with water (300.0
mL) followed by acidification by drop wise addition of conc. HCl (60.0 mL). The
resulting precipitate was filtered, washed with D.M. water (100.0 mL x 2)
followed by cyclohexane (50.0 mL x 2) and dried under vacuum at 50 °C to give
chloro acid derivative 47 (82.5 g, 88%).
mp: 154−157 °C; m/z: 213.0 (M+H)
+ ;
1H NMR (400 MHz, DMSO_d6): δ
2.15−2.21 (m, 2H), 3.79 (t, J = 6.4 Hz, 2H), 4.15 (t, J = 6.0 Hz, 2H), 7.03 (d, J =
8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 12.64 (brs, 1H); 13
C NMR (100 MHz,
DMSO_d6): 31.9, 42.4, 65.1, 114.9, 123.3, 132.1, 162.7, 167.8.
Preparation of 3-[4-(3-chloropropoxy)benzoyl]2-n-butyl-1-benzofuran-5-yl-
1H-isoindole-1,3(2H)dione (56).
O
N
O
O
Cl
O
O
Procedure−I : Friedel-Craft acylation using SnCl4 as lewis acid.
To the mixture of phthalimido derivative 55 (100.0 g, 0.313 mol) in DCM (250.0
mL), anhydrous SnCl4 was added at 5 °C. Acid chloride 52 (76.52 g, 0.328 mol)
in DCM (250.0 mL) and added slowly to the reaction mixture at 0 to 5 °C.
Reaction mixture was stirred for 1 h at 5 °C followed by at 25 to 30 5
°C for 1 h.
The reaction mixture was quenched by pouring on to ice cold water (450.0 mL)
by keeping temperature of reaction mixture below 20 °C. Layers were separated
after stirring for 30 min. Organic layer was consecutively washed with 2.0 N HCl
solution (450 mL x 2) and 5.0% NaHCO3 solution (450.0 mL). Solvent was
distilled off and residue was slurred with MeOH (800.0 mL) and solids were
52
filtered, washed with MeOH (200.0 mL) and dried at 45 °C to furnish chloro
compound 56 (129.5 g, 79.0%).
Procedure−II : application of Eaton’s reagent.
Eaton‟s reagent was prepared by adding P2O5 (111.2 g, 0.783 mol) portion wise to
methane sulfonic acid (425.0 mL) under nitrogen atmosphere and stirred for 30
min at 25 to 35 °C. To this, chloro acid 47 (70.33 g, 0.328 mol) was added and
allowed to stir for 15 min, and then phthalimido derivative 55 (100.0 g, 0.313
mol) was charged and stirred for 1 h at 35 °C. After complete consumption of
starting material, reaction was quenched by pouring reaction mass in to a mixture
of water (1.0 L) and DCM (200.0 mL) below 15 °C and layers were separated.
Organic layer was washed with 5% NaHCO3 solution (2 x 400.0 mL) followed by
water wash (400.0 mL). DCM was distilled off and the residue was slurred with
methanol (800.0 mL) and the solids were filtered, washed with methanol (200.0
mL) and dried at 45 °C to furnish chloro compound 56 (121.2 g, 76.0%).
mp: 109−110 °C; m/z: 516.1 (M+H)
+ ;
1H NMR (400 MHz, CDCl3): δ 0.90 (t, J =
7.4 Hz, 3H), 1.32−1.41(m, 2H), 1.73−1.80 (m, 2H), 2.22−2.29 (m, 2H), 2.95 (t, J
= 7.5 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 4.20 (t, J = 5.8 Hz, 2H), 6.97 (d, J = 8.8
Hz, 2H), 7.29 (dd, J = 8.7 Hz, J = 2.1 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.59 (d,
J = 8.7 Hz, 1H), 7.76−7.78 (m, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.86−7.94 (m, 2H);
13C NMR (100 MHz, CDCl3): 13.55, 22.16, 27.70, 29.93, 31.88, 41.15, 64.38,
111.40, 114.15, 116.75, 120.11, 123.15, 123.47, 126.98, 127.66, 131.49, 131.57,
134.15, 152.65, 162.47, 165.90, 167.22, 189.46; Anal. Calcd for C30H26ClNO5 :
C, 69.83; H, 5.08; N, 2.71 Found: C, 70.08; H, 5.09; N, 2.72.
53
Preparation of 3-[4-(3-di-n-butyl amino propoxy)benzoyl]2-n-butyl-1-
benzofuran-5-yl-1H-isoindole-1,3(2H)dione hydrochloride (57).
O
N
O
O
N
O
O
.HCl
Chloro compound 56 (100.0 g, 0.193 mol), KI (32.2 g, 0.194 mol), TBAB (5.0 g,
0.015 mol), Di-n-butyl amine (50.1 g, 0.388 mol) and DMF (150.0 mL) were
heated to 85 °C for 14 h. Reaction mixture was cooled to 25 °C and water (600.0
mL), DCM (150.0 mL) were added. Layers were separated, organic layer was
sequentially washed with 2.0 N HCl (2 x 150 mL), D.M. water (2 x 500.0 mL)
DCM was distilled completely and residue was diluted with IPA (400.0 mL)
followed by cooling of reaction mass to 0 to 5 °C. This was done to crystallize
the product. The precipitated solids were filtered, washed with chilled IPA (2 x
50.0 ml) and dried under vacuum at 50 °C, in this manner hydrochloride salt of
compound 57 was afforded as off- white solid (100.0 g, 85.0%).
mp: 109−110 °C; m/z: 609.1 (M+H)
+ ;
1H NMR (400 MHz, DMSO_d6): δ 0.80 (t,
J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H), 1.21−1.36 (m, 6H), 1.57−1.71 (m, 6H),
2.08−2.18 (m, 2H), 2.81 (t, J = 7.4 Hz, 2H), 3.05−3.10 (m, 4H), 3.22−3.26 (m,
2H), 4.17 (t, J = 5.8 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.42 (dd, J = 8.7 Hz, J =
2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.79−7.85 (m, 3H), 7.88−7.96 (m, 4H), 9.47
(brs, 1H); 13
C NMR (100 MHz, DMSO_d6): 13.46, 13.57, 19.46, 21.65, 23.02,
25.05, 27.37, 29.46, 48.96, 51.93, 65.28, 111.59, 114.65, 116.51, 120.15, 123.45,
124.47, 127.19, 127.76, 131.15, 131.54, 131.60, 134.75, 152.35, 162.34, 164.72,
167.36, 189.30; Anal. Calcd for C38H44N2O5.HCl : C, 70.74; H, 7.03; N, 4.34
Found: C, 70.58, H, 7.09, N, 4.22.
54
Preparation of 5-Amino-3-[4-(3-di-n-butyl amino propoxy)benzoyl]2-n-butyl-
1-benzofuran dioxalate (58).
O
NH2
O
ON
.2COOH
COOH
Procedure−I : Deprotection of 3-[4-(3-di-n-butyl amino propoxy)benzoyl]2-n-
butyl-1-benzofuran-5-yl-1H-isoindole-1,3(2H)dione hydrochloride.
Amino compound 57 (100.0 g, 0.164 mol) was added to the mixture of IPA
(400.0 mL) and methylamine 40% aqueous solution (100.0 mL) and resulting
suspension was heated for 1 h at 75 °C followed by distillation of excess
methylamine and solvent under reduced pressure. The residue was diluted with
IPA (400.0 mL) and oxalic acid dihadrate (41.3 g, 0.328 mol) was added and
stirred at 65 °C for 30 min. The reaction mixture was cooled to 5
°C and stirred
for 1 h. The precipitated solids were filtered and washed with IPA (100.0 mL)
followed by acetone (100.0 mL) and dried at 50 °C to furnish dioxalate salt 58
(97.0 g, 90.0%).
Procedure−II : One pot preparation from 3-[4-(3-chloropropoxy)benzoyl]2-
n-butyl-1-benzofuran-5-yl-1H-isoindole-1,3(2H)dione.
Chloro compound 56 (100.0 g, 0.193 mol), KI (32.2 g, 0.194 mol), TBAB (5.0 g,
0.015 mol), Di-n-butyl amine (50.1 g, 0.388 mol) and DMF (150.0 mL) were
heated to 85 °C for 14 h. Reaction mixture was cooled to 25 °C, water (600.0
mL), DCM (150.0 mL) were added. Layers were separated, organic layer was
sequentially washed with 2.0 N HCl (150 mL), D.M. water (500.0 mL x 2)
55
followed by saturated NaHCO3 solution (250.0 mL). DCM was distilled
completely to afford amino compound 57 as oil. IPA (400.0 mL) followed by
methylamine 40% aqueous solution (100.0 mL) was added and mixture was
heated for 1 h at 75 °C. Reaction mixture was concentrated under vacuum. The
residue was diluted with IPA (500.0 mL) and oxalic acid dihadrate (49.0 g, 0.388
mol) was added and stirred at 65 °C for 30 min. The reaction mixture was cooled
to 5 °C and stirred for 1 h. The predicated solids were filtered and washed with
IPA (100.0 mL) followed by acetone (100.0 mL) and dried at 50 °C to furnish
crude dioxalate salt 58 (105.0 g, 82.0%) with purity 95%.
Recrystalization of crude dioxalate salt 58 from MeOH results in pure product
with purity more than 99% by HPLC and individual impurity less 0.5% (90.0 g,
70.0%).
mp: 166−170 °C; m/z: 479.2 (M+H)+
; 1H NMR (400 MHz, DMSO_d6): δ 0.79 (t,
J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 6H), 1.19−1.24 (m, 2H), 1.28−1.37 (m, 4H),
1.57−1.65 (m, 6H), 2.12−2.18 (m, 2H), 2.72 (t, J = 7.5 Hz, 2H), 3.04−3.09 (m,
4H), 3.20−3.24 (m, 2H), 4.17 (t, J = 5.9 Hz, 2H), 6.53 (d, J = 2.0 Hz, 1H), 6.59
(dd, J = 8.7 Hz, J = 2.2 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.7 Hz,
1H), 7.76 (d, J = 8.8 Hz, 2H); 13
C NMR (100 MHz, DMSO_d6): 13.63, 13.73,
19.64, 21.85, 23.16, 25.17, 27.44, 29.75, 49.07, 52.05, 65.39, 107.01, 111.55,
114.73, 116.46, 127.61, 131.59, 131.65, 141.06, 148.03, 162.35, 163.68, 164.22,
190.10; Anal. Calcd for C34H46N2O11 : C, 61.99; H, 7.04; N, 4.25 Found: C,
61.91; H, 7.15; N, 4.41.
56
Preparation of Dronedarone Hydrochloride (2).
O
O
ON
NHS
O O
.HCl
Dioxalate salt 58 (100.0 g, 0.152 mol) was added portionwise to the stirred
mixture of water (300.0 mL) DCM (300.0 mL) and NaHCO3 (56.6 g, 0.674 mol).
Above suspension was stirred for 30 min. Inorganic solids were filtered and
layers were separated. Organic layer containing precursor free amine was washed
with water (2 x 200.0 mL). DCM was distilled out. To this residue toluene
(300.0 mL) was added followed by Et3N (23.0 g, 0.227 mol) and chilled at -5 °C.
Methane sulfonyl chloride (18.3 g, 0.159 mol) was added dropwise at -5 to 5 °C
and stirred for 30 min. After completion of reaction on TLC, reaction mass was
quenched by adding 5.0% aqueous NaHCO3 (300.0 mL) and layers were
separated, washed with water (200.0 mL). Toluene was distilled out and the
residue was stirred with a mixture of DCM (300.0 mL), conc. HCl (30.0 mL) and
D. M. water (300.0 mL) for 30 min.
After layer separation, organic layer was washed with D. M. water (200.0 mL x
2). DCM was distilled out and to the residue mixture of ethyl acetate and IPA
(1.0 L, 9:1) was added and stirred at 25 °C for 4 h. The reaction mixture was
cooled at 5 °C and stirred for 2 h. Suspension was filtered to afford Dronedarone
Hydrochloride crude (67.0 g, 75.0%). Recrystallisation of crude product from
acetone results in Pure Dronedarone Hydrochloride (2) with purity more than
99.5% by HPLC and any individual impurity less than 0.10% (54.0 g, 60.0%).
57
mp: 143 °C; m/z: 557.3 (M+H)+
; 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J = 7.4
8Hz, 3H), 0.9 (t, J = 7.3 Hz, 6H), 1.34−1.45 (m, 6H), 1.72−1.84 (m, 6H),
2.38−2.45 (m, 2H), 2.91 (s, 3H), 2.96 (t, J = 7.7 Hz, 2H), 3.03−3.07 (m, 4H),
3.22−3.27 (m, 2H), 4.24 (t, J = 5.4 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 7.18 (d, J =
2.1 Hz, 1H), 7.31 (dd, J = 8.8 Hz, J = 2.1 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H),
7.66 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 11.93 (s, 1H); 13
C NMR (100 MHz,
CDCl3):13.23, 13.35, 19.70, 21.95, 23.32, 24.75, 27.57, 29.67, 38.15, 49.84,
52.08, 64.72, 111.12, 113.99, 115.18, 116.38, 119.75, 127.42, 131.30. 131.50,
133.06, 151.14, 161.77, 165.55, 189.79; Anal. Calcd for C31H45ClNO5S : C,
62.77; H, 7.56; N, 4.72; S, 5.40 Found: C, 62.83; H, 7.46; N, 4.91; S, 5.60.
Preparation of Disulfonamide impurity (59).
O
O
ON
NS
O O
S
O
O
Dioxilate salt 58 (10.0 g, 0.015 mol) was added portion wise in to the stirred
mixture of water (30.0 mL), DCM (30.0 mL) and NaHCO3 (5.6 g, 0.067 mol).
Suspension was stirred for 30 min. and resulting inorganic solids were filtered
followed by layer separation. Organic layer was washed with D. M. water (20.0
mL x 2) and dried over MgSO4. To the reaction mass Et3N (4.5 g, 0.045 mol)
was added and solution was chilled at -5 °C. Methane sulfonyl chloride (4.3 g,
0.037 mol) was added dropwise at -5 to 5 °C and stirred for 30 min. After
complete conversion on TLC, reaction was quenched by adding saturated
NaHCO3 solution (30.0 mL) and layers were separated; organic layer was washed
with D.M. water (20.0 mL). DCM was distilled out and resulting product was
purified by column chromatography. (Eluting phase:-m CHCl3: MeOH; 99:1) to
afford disulfonamide impurity 59 as gummy solid (6.2 g, 65.0%).
58
m/z: 635.0 (M+H)+
; 1H NMR (400 MHz, CDCl3): δ 0.85−0.92 (m, 9H),
1.28−1.37 (m, 6H), 1.38−1.46 (m, 4H), 1.67−1.75 (m, 2H), 1.94−1.99 (m, 2H),
2.45 (t, J = 7.4 Hz, 4H), 2.63 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 7.4 Hz, 2H), 3.35 (s,
6H), 4.09 (t, J = 6.1 Hz, 2H), 6.95 93 (d, J = 8.6 Hz, 2H), 7.25 (dd, J = 8.6 Hz, J
= 1.7 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 8.6
Hz, 2H); 13
C NMR (100 MHz, CDCl3):13.52, 13.96, 20.55, 22.18, 26.76, 27.83,
28.96, 29.91, 42.50, 50.25, 53.75, 66.43, 111.92, 114.18, 116.76, 123.85, 126.48,
128.44, 128.89, 131.00, 131.66, 153.90, 163.23, 166.16, 189.30.
Spectra
59
1H NMR spectrum of Compound 39 in CDCl3
13C NMR spectrum of Compound 39 in CDCl3
60
Mass spectrum of compound 39
1H NMR spectrum of Compound 40 in CDCl3
61
13C NMR spectrum of Compound 40 in CDCl3
Mass spectrum of compound 40
62
1H NMR spectrum of Compound 30 in DMSO_d6
13
C NMR spectrum of Compound 30 in DMSO_d6
63
Mass spectrum of compound 30
1H NMR spectrum of Compound 55 in CDCl3
64
13C NMR spectrum of Compound 55 in CDCl3
Mass spectrum of compound 55
65
1H NMR spectrum of Compound 48 in CDCl3
13C NMR spectrum of Compound 48 in CDCl3
66
Mass spectrum of compound 48
1H NMR spectrum of Compound 47 in DMSO_d6
67
13C NMR spectrum of Compound 47 in DMSO_d6
Mass spectrum of compound 47
68
1H NMR spectrum of Compound 56 in CDCl3
13
C NMR spectrum of Compound 56 in CDCl3
69
Mass spectrum of compound 56
1H NMR spectrum of Compound 57 in DMSO_d6
70
13
C NMR spectrum of Compound 57 in DMSO_d6
Mass spectrum of compound 57
71
1H NMR spectrum of Compound 58 in DMSO_d6
13
C NMR spectrum of Compound 58 in DMSO_d6
72
Mass spectrum of compound 58
1H NMR spectrum of Compound 2 in CDCl3
73
13
C NMR spectrum of Compound 2 in CDCl3
Mass spectrum of compound 2
74
1H NMR spectrum of Compound 59 in CDCl3
13
C NMR spectrum of Compound 59 in CDCl3
75
Mass spectrum of compound 59
References
76
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