WO2015031352..........PROCESS FOR PREPARING DRONEDARONE AND SALTS THEREOF .

(WO2015031352) PROCESS FOR PREPARING DRONEDARONE AND SALTS THEREOF . 

PROCESS FOR PREPARING DRONEDARONE AND SALTS THEREOF (Fri, 06 Mar 2015) 
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https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015031352&recNum=1&docAn=US2014052692&queryString=EN_ALL:nmr%20AND%20PA:(gilead%20sciences)&maxRec=867

GILEAD SCIENCES, INC. [US/US]; 333 Lakeside Drive Foster City, CA 94404 (US)
Inventors:	CHAN, Johann; (US). VITALE, Justin; (US)
Agent:	GINAH, Francis O.; (US)
Priority Data:	61/870,632 27.08.2013 US 61/903,285 12.11.2013 US
Title	(EN) PROCESS FOR PREPARING DRONEDARONE AND SALTS THEREOF (FR) PROCÉDÉ DE SYNTHÈSE DE DRONÉDARONE ET DES SELS DE CELLE-CI
Abstract:	(EN)The present disclosure relates to processes for preparing dronedarone or pharmaceutically acceptable salts thereof. (FR)La présente invention concerne des procédés de synthèse de la dronédarone ou des sels pharmaceutiquement acceptables de celle-ci.

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:

t



Example 1
/. Friedel Crafts reaction of Compound (1) to provide Compound (3)


To a solution of compound (1) (1 equiv) and 4-fluorobenzoyl chloride (1.2 equiv) in CH2CI2 (10 volumes) at ambient temperature is added A1C1₃ (0.5 equiv). The reaction is stirred at ambient temperature and then heated under reflux. The reaction mixture is diluted with CH2CI2 (20 volumes) and quenched by the addition of ice-cold water (30 volumes). Following phase separation, the organic phase is dried over Na₂S0₄, filtered and concentrated under reduced pressure. The crude residue is purified by chromatography on silica gel (10 to 50% CH2CI2 in heptane) to provide compound (3). Ή NMR (400 MHz, DMSO-d₆) δ ppm 7.82 (dd, J= 8.6, 5.6 Hz, 2H), 7.62 (d, J= 8.6 Hz, 1H) 7.43 - 7.53 (m, 2H), 7.37 (t, J = 8.8 Hz, 2H), 2.72 (t, J= 7.5 Hz, 2H), 1.71 - 1.49 (m, 2H), 1.29 - 1.09 (m, 2H), 0.74 (t, J= 7.3 Hz, 3H); ^I9F NMR (376 MHz, DMSO-d₆) 5 -106.39.
11. Cu-catalyzed sulfonamide coupling of compound (3) to provide compound (4)


(3) (4)
Compound (3) (1 equiv), N-benzylniethane sulfonamide (3 equiv), 2CO3 (3 equiv), Cul (0.5 equiv), acetonitrile (7 volumes) and toluene (7 volumes) are combined and the resulting mixture is sparged with N₂. NN'-Dimethylethane-l,2-diamine (10 equiv.) is then added, and the reaction mixture is heated at about 80 °C for about 3 hours. The reaction mixture is cooled to ambient temperature and filtered through a pad of celite. The celite cake is rinsed with acetonitrile (13 volumes) and the filtrate is concentrated under reduced pressure. The residue is dissolved in isopropyl acetate (33 volumes), washed with aqueous HC1 and 20% aqueous NaCl, dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The crude residue is purified by chromatography on silica gel to afford compound (4).
III. Nucleophilic aromatic substitution of compound (4) to provide compound (5)


N-benzyl-N-(2-butyl-3-(4-fluorobenzoyl)benzofuran-5-yl)methanesulfonamide (4, 29.0 mg, 0.06 mmol) was dissolved in NMP (0.5 ml) and the solution was added to a pre-warmed mixture of 3-(dibutylamino)propan-l -ol (33.7 mg, 0.18 mmol) and NaOt-Bu (17.3 mg, 0.18 mmol) in NMP (0.5 ml) at about n60 °C. The resulting reaction mixture was stirred at about 60 °C and the most of starting material (4) was converted by HPLC after 1.5 hours. The in-process sample at about 1.5 hour indicated target molecule (5) formation: LCMS [MH⁺] : m/z = 647.40, t_R = 7.80 min. IV. Conversion of compound (5) to compound (I)


An isopropanol solution of compound (5) (1 equiv) and Pd-C (10 weight %) are agitated under a hydrogen atmosphere (20-45 psig). The catalyst is filtered, and the solution is treated with aqueous HC1 (1.2 equiv). The resulting solids are isolated by filtration to afford compound (I). V. Cu-catalyzed sulfonamide coupling of compound (3) to provide compound (6)


(3) (6)
Compound (3) (1 equiv.), N-boc-methanesulfonamide (3 equiv.), K₂CO₃ (3 equiv), Cul (0.5 equiv), acetonitrile (7 volumes) and toluene (7 volumes) are combined and the resulting mixture is sparged with N₂. N,N'-dimethylethane-l ,2-diamine (10 equiv.) is then added, and the reaction mixture is heated at about 80 °C for about 3 hours. The reaction mixture is cooled to ambient temperature and filtered through a pad of celite. The celite cake is rinsed with acetonitrile (13 volumes) and the filtrate is concentrated under reduced pressure. The residue is dissolved in isopropyl acetate (33 volumes), washed with aqueous HC1 and 20% aqueous NaCl, dried over Na₂S04, filtered, and concentrated under reduced pressure. The crude residue is purified by chromatography on silica gel to afford compound (6).
VI. Nucleophilic aromatic substit d (6) to provide compound (7)


(6) (7)
A mixture of dibutylamino propanol (3 equiv), sodium iert-butoxide (3 equiv) and NMP (10 volumes) is heated at about 60 °C under N₂ for about 10 minutes. A solution of compound (6) (1 equiv) in NMP (6 volumes) is added dropwise to the reaction mixture over about 3 minutes. The transfer is completed with additional NMP. The reaction mixture is heated at about 60 °C for about 25 minutes, then cooled to about 0 °C and diluted with isopropyl acetate. To the mixture is then added aqueous HQ. Following separation of the phases, the organic layer is washed with water, dried over Na₂SC>4, filtered and concentrated. The crude product is purified by chromatography on silica gel to afford compound (7).
VII. Conversion of compound (7) to compound (I)

(7) (I)
An isopropanol solution of compound (7) (1 equiv) is treated with concentrated aqueous HCl
(2.2 equiv). The resulting solids are isolated by filtration to afford compound (1).

1. 1. 
2. Foster City

Daiichi Sankyo Co. v. Matrix Laboratories, Ltd. (Fed. Cir. 2010)

In Daiichi Sankyo Co. v. Matrix Laboratories, Ltd., decided last Thursday, the Federal Circuit affirmed a determination by the District Court for the District of New Jersey that Matrix Laboratories, Ltd., Mylan Inc., Mylan Laboratories, Inc., and Mylan Pharmaceuticals, Inc. ("Mylan") failed to establish a prima facie case of obviousness with respect to claim 13 of U.S. Patent No.5,616,599.  Daiichi Sankyo Company, Ltd. and Daiichi Sankyo, Inc. own the '599 patent, which relates to 1-biphenylmethylimidazole compounds and their use as angiotensin receptor blockers (ARBs) for the treatment of high blood pressure.  Claim 13 of the '599 patent encompasses olmesartan medoxomil, an ARB that is marketed by Daiichi as the active ingredient in Benicar®, Benicar HCT®, and Azor®.

The use of ARBs to control blood pressure can be traced back to work done in the 1970s and 1980s by Takeda Pharmaceutical Co. Ltd., which developed a class of compounds comprising an imidazole ring with other chemical moieties bonded to the five positions of the ring.  One such compound, Takeda's S-8307, has the chemical structure:

Using Takeda's compounds as leads, E. I. du Pont de Nemours and Company sought to develop compounds having inreased angiotensin receptor binding, and therefore, better ARB activity.  DuPont modified S-8307 to develop the compound losartan, which has ten-fold higher binding than Takeda's compounds.  DuPont's losartan has the chemical structure:

DuPont disclosed losartan in U.S. Patent No. 5,138,069 along with more than 400 structurally related ARBs, including Example 118, which has the chemical structure:

Based on DuPont's success with losartan, a number of pharmaceutical companies, including Daiichi, initiated efforts to identify even better ARBs.  Daiichi's work led to the synthesis of olmesartan, the active metabolite of olmesartan medoxomil, which differs from losartan in that it has a hydrophilic, hydroxy-isopropyl group at the 4-position of the imidazole ring instead of a lipophilic, chlorine atom (like Example 118 above), and a carboxy group masked by a medoxomil prodrug substituent at the 5-position of the ring instead of a hydroxymethyl group.  Olmesartan medoxomil and olmesartan have the chemical structures:

The closest prior art structure to Daiichi's olmesartan is DuPont's Example 6, disclosed in U.S. Patent No. 5,137,902, which differs from olmesartan in that it lacks a single oxygen atom at the 4-position of the imidazole ring.  DuPont's Example 6 has the chemical structure (wherein the circled hydrogen atom in Example 6 is an -OH in olemsartan):

Seeking approval to market generic olmesartan medoxomil, Mylan filed multiple ANDAs with the FDA.  In response to Mylan's ANDA filings, Daiichi brought suit against Mylan for infringement of claim 13 of the '599 patent.  The parties stipulated to infringement, leaving Mylan's counterclaim that claim 13 would have been obvious in light of:  (1) the ARBs disclosed in DuPont's '902 patent, (2) Example 118 in DuPont's '069 patent, and (3) the well-known use of medoxomil as a prodrug.  In particular, Mylan contended that one of skill in the art would have been motivated to select the ARBs disclosed in DuPont's '902 patent as lead compounds, and then modify the lipophilic alkyl groups at the 4-position of those compounds with olmesartan's hydrophilic hydroxyalkyl group in view of Example 118.

Following a bench trial, the District Court held that claim 13 of the '599 patent was not invalid as obvious, finding that Mylan had failed to show by clear and convincing evidence that a skilled artisan would have chosen the ARBs disclosed in DuPont's '902 patent as lead compounds, that the structure of the '902 patent compounds differed significantly from olmesartan medoxomil, and that Mylan had failed to prove that a skilled artisan would have been motivated to modify the 4- and 5-positions of the '902 patent compounds to obtain olmesartan medoxomil.  In particular, the District Court determined that the '069 patent and its ARBs taught away from the use of a hydrophilic group at the 4-position and from any expectation that the use of a hydrophilic group would generate an ARB with significantly improved biological properties, and further, that converting olmesartan into a prodrug was a disfavored and unpredictable approach and that medoxomil was a disfavored prodrug.  The District Court also found that secondary considerations favored a finding of nonobviousness; specifically that olmesartan medoxomil's enhanced potency constituted evidence of unexpected results and that Daiichi's Benicar® enjoyed commercial success despite being the seventh ARB on the market.

In affirming the District Court's finding of nonobviousness, the Federal Circuit agreed with Daiichi in determining that Mylan failed to show (1) that one of ordinary skill in the art would have been motivated to select the ARBs disclosed in DuPont's '902 patent as lead compounds or (2) that the skilled artisan would have been motivated to modify the '902 patent compounds to synthesize olmesartan medoxomil.  The Court began its analysis by citingEisai Co. Ltd. v. Dr. Reddy's Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008), andTakeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007), for the proposition that:

Proof of obviousness based on structural similarity [between claimed and prior art compounds] requires clear and convincing evidence that a medicinal chemist of ordinary skill would have been motivated to select and then to modify a prior art compound (e.g., a lead compound) to arrive at a claimed compound with a reasonable expectation that the new compound would have similar or improved properties compared with the old.

With respect to the issue of lead compound selection, the panel countered Mylan's argument that because the '902 patent compounds are the closest prior art, this should have been dispositive of the lead compound issue, pointing out that such argument "runs contrary to our case law."  The Court noted that "[i]nTakeda, we upheld a district court's finding that one of skill in the art would not have chosen the structurally closest prior art compound, compound b, as the lead compound in light of other compounds with more favor-able characteristics," adding that the Court's cases "illustrate that it is the possession of promising useful properties in a lead compound that motivates a chemist to make structurally similar compounds."  Citing Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358 (Fed. Cir. 2008), the Court explained that "attribution of a compound as a lead compound after the fact must avoid hindsight bias; it must look at the state of the art at the time the invention was made to find a motivation to select and then modify a lead compound to arrive at the claimed invention" (emphasis in original).  Thus, the selection of a lead compound "depends on more than just structural similarity, but also knowledge in the art of the functional properties and limitations of the prior art compounds," and therefore, "[p]otent and promising activity in the prior art trumps mere structural relationships."

Turning to the issue of motivation to modify, the panel noted that the vast majority of compounds disclosed in the '069 patent contain a lipophilic group at the 4-position of the imidazole ring, and that only four (Examples 342, 329, 118, and 335) have a hydrophilic group like olmesartan medoxomil.  According to the Court, "[t]he few compounds with hydrophilic groups at the 4-position are drowned out by the sea of 4-lipophilic compounds, which are the essence of what the ’069 patent teaches."  In addition, the Court observed that binding affinity analyses comparing the '069 patent compounds that differed only at the 4-position confirm the preference for lipophilicity at that position.  The panel determined that:

Altogether, the '069 patent's [structural-activity relationship] data and the structure of other second-generation ARBs counter any notion that one of skill in the art would have been motivated to modify the '902 compounds' lipophilic alkyl groups to a hydrophilic group.  Such a holding would have been based on hindsight.

The panel therefore affirmed both the District Court's finding that Mylan had failed to establish that a skilled artisan would have selected the '902 patent ARBs as lead compounds and the lower court's finding that a skilled artisan would have modified the '902 patent ARBs at the 4-position of the imidazole ring to obtain olmesartan medoxomil.  As a result, the Federal Circuit affirmed the District Court's determination that claim 13 of the '599 patent was not shown to be invalid as obvious.

Daiichi Sankyo Co. v. Matrix Laboratories, Ltd. (Fed. Cir. 2010)
Panel: Circuit Judges Lourie, Friedman, and Linn
Opinion by Circuit Judge Lourie