CLIAMS:0 ,TagSPECI:FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
PROVISIONAL SPECIFICATION
(SECTION 10, RULE 13)
“AN IMPROVED PROCESS FOR PREPARATION OF CINACALCET
HYDROCHLORIDE”
DISHMAN PHARMACEUTICALS & CHEMICALS LIMITED
A Company Incorporated Under The Indian Companies Act
Bhadr-Raj Chambers, Swastik Cross Roads,
Navrangpura, Ahmedabad-380 009,
Gujarat State, India
The following specification particularly describes the invention:
2
FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of
cinacalcet hydrochloride with high yields. In particular, the present
invention relates to an improved in-situ process for preparation of
cinacalcet hydrochloride with high yield and purity without isolation of
intermediates.
BACKGROUND AND PRIOR ART
Cinacalcet, chemically known as (R)-a-methyl-N-[3-[(3-
trifluoromethyl)phenyl]propyl]-1-napthalenemethanamine, is known for
anti-hyperparathyroid action and is marketed as the hydrochloride
formula (1). Cinacalcet hydrochloride is commercially marketed under
the brand name of SENSIPAR which is useful for the treatment of
hyperparathyroidism and the preservation of bone density in patients
with kidney failure or hypercalcemia due to cancer. It is the first drug in
a class of compounds known as calcimimatics, approved by the FDA.
Formula (1)
F3C
HN
HCl
Calcimimatics are a class of orally active molecules that decrease the
secretion of parathyroid hormone (“PTH”) by activating calcium receptors.
Calcimimetic agents increase the sensitivity of this receptor to calcium,
which inhibits the release of parathyroid hormone and lowers
parathyroid hormone levels within a few hours. Calcimimatics are used
to treat hyperparathyroidism, a condition characterized by the over
secretion of PTH that results when calcium receptors on parathyroid
glands fail to respond properly to calcium in the bloodstream. Elevated
3
levels of PTH, an indicator of secondary hyperparathyroidism, are
associated with altered metabolism of calcium and phosphorus, bone
pain, fractures, and an increased risk for cardiovascular death.
Cinacalcet hydrochloride is approved for treatment of secondary
hyperparathyroidism in patients with chronic kidney disease on dialysis.
Treatment with cinacalcet hydrochloride lowers serum levels of PTH as
well as the calcium or phosphorous ion product, a measure of the
amount of calcium and phosphorous in the blood.
In the United States, it is marketed under the name of Sensipar® and in
Europe, it is marketed under the name of Mimpara® and Parareg®. It is
available as 33, 66 and 99 mg tablets of cinacalcet hydrochloride
equivalent to 30, 60 and 90 mg of cinacalcet free base respectively.
The synthetic procedure as per U.S. Patent No. 6,211,244 describes
cinacalcet and its pharmaceutical acceptable acid chloride addition salt
and process for the preparation of the same in analogues way. The
synthetic procedure is illustrated in scheme 1.
F3C +
F3C Ti(O-i-Pr)4 N
Cinacalcet iso-imine
Racemic-Cinacalcet base
Formula (1)
O
NH2
1-acetyl naphthalene
CH3
Sodium
cyanoborohydride Methanol
F3C
HN
CH3
(R) - Cinacalcet Base Chiral LC
Scheme (1)
4
According to this patent, Cinacalcet is produced by reacting 1-acetyl
naphthalene with 3-(3-(trifluoromethyl)phenyl)propylamine in the
presence of titanium isopropoxide to produce an imine, followed by
treatment with methanolic sodium cyanoborohydride to obtain racemic
base and further resolution of the racemic Cinacalcet base by chiral
liquid chromatography.
Further Drugs of the Future 2002, 27(9), 832 reports a process scheme-
2 for the preparation of Cinacalcet starting from 3-[3-(trifluoromethyl)
phenyl]propionaldehyde of formula (2) and (R)-1-(1-napthyl)ethylamine of
formula (3)
F3C +
H2N F3C
Ti(O-i-Pr)4 N
Cinacalcet imine
O
Formula (3)
CH3
Sodium
cyanoborohydride Ethanol
(R) - Cinacalcet Base
Formula (2)
Scheme (2)
by formation of an imine intermediate and subsequent reduction with
sodium cyanoborohydride in ethanol.
U.S Pat. No. 6,211,244 discloses an additional process for the synthesis
of Cinacalcet. This process involves treating 3-
trifluoromethylcinnamonitrile, which can be prepared as disclosed in
U.S. Pat. No. 4,966,988, with diisobutyl aluminium hydride, followed by
treating the intemediate aluminium-imine complex with (R)-1-(1-
5
naphthyl)ethlamine, and reducing the intermediate imine with ethanolic
sodium cyanoborohydride, according to the following Scheme (3).
F3C CN
H2N
F3C
N
3-Trifluoromethyl cinnamonitrile
(R)-1-(1-napthyl)ethylamine
Cinacalcet imine
(R) - Cinacalcet base
Formula (3)
F3C
Al(i-Bu)2H
DCM, 0oC
Al-imine complex
N
Al(i-Bu)2
DCM
NaBH3CN
Ethanol
Scheme (3)
All these process however, require the use of reagents such as titanium
isopropoxide which is highly hygroscopic and expensive, as well as toxic,
and ethanolic or methanolic sodium cyanoborohydride, which is highly
toxic and flammable and not environmentally friendly, making the
processes difficult to apply on industrial scale.
WO2006/125026 discloses synthetic procedure for preparation of
cinacalcet. This procedure involves the Heck coupling of 1-bromo-3-
trifluoromethyl benzene with acrolein dialkyl acetal to get a mixture of
unsaturated acetal and saturated ester. The mixture of compounds was
hydrolyzed to get a mixture of unsaturated aldehyde and saturated ester
was subjected for double bond reduction it furnished a mixture of
saturated aldehyde and saturated ester. Similarly when the mixture of
unsaturated aldehyde and saturated ester was subjected for carbonyl
6
moiety reduction it furnished a mixture of unsaturated alcohol. The
saturated aldehyde and saturated ester was subjected to reduction of
carbonyl moiety and the mixture of unsaturated alcohol and saturated
alcohol were subjected to reduction of double bond to get the saturated
alcohol according to Scheme (4).
F3C Br +
OR
OR
F3C
3-bromotrifluorotoluene
Hack coupling
reaction
OR
OR
+ O
F3C
OR
H+
O
F3C
O
F3C
OR
+
O
F3C
O
F3C
OR
+
F3C OH + F3C OH
F3C
OH
Reduction of carbonyl
moiety
Reduction of double
bond
Reduction of carbonyl
moiety
Reduction of double
bond
Scheme (4)
According to Scheme (4) the Heck reaction involves palladium catalyst
which is a precious metal catalyst. The condensation of 1-bromo-3-
trifluoromethyl benzene with acrolein dialkyl acetal gave two products.
The formation of multiple products during each conversion to get the
alcohol does not make the process feasible from synthetic point of view.
WO2006/125026 also discloses another strategy for the preparation of
cinacalcet. This procedure involves the Heck coupling of 1-bromo-3-
trifluoromethyl benzene with ethyl acrylate to get the unsaturated ester,
which was subjected to reduction of double bond and reduction of
7
carbonyl moiety to get the saturated alcohol, which was converted to a
compound with leaving group and condensed with (R)-1-(1-naphthyl)
ethyl amine to get cinacalcet base according to scheme (5).
F3C Br
OR
OR
F3C
3-bromotrifluorotoluene
Hack coupling
reaction
O
F3C
OR
F3C
OH F3C
OH
F3C
HN
Reduction of carbonyl
moiety
Reduction of double
bond
O
Reduction of double
bond
F3C
Base H2N + X
(X = Halogen
Cinacalcet Base
Reduction of carbonyl
moiety
Scheme (5)
The synthesis reported above in scheme (5) also involves a Heck coupling
reaction, which involves the use of expensive palladium catalyst which is
not viable.
WO2008/117299 provided a process for the preparation cinacalcet
according to scheme (6). The process comprises, Condensation of
malonic acid and 3-trifluoromethyl benzaldehyde in first step, it has
lower yield to produce unsaturated acid and in second step expensive
palladium carbon, a metal catalyst is used which makes the invention
non-viable to be used in industries.
8
F3C CHO
OH
F3C
Pyridine
Piperidine
O
F3C
OH
F3C
HN
O
Pd-C
Methanol
H2N
HO OH
O O
O
F3C
HN
NaBH4 , I2
Cinacalcet base
SOCl2,
Toluene,
DMF
3-Trifluoromethyl
benzaldehyde Unsaturated acid Saturated acid
Amide
Scheme (6)
U.S. Pat. No. 7,393,967 disclosed a process for the preparation of
cinaclacet base comprising of Hack coupling reaction of 3-
bromotrifluorotoluene with an allyl amine in the presence of a catalyst
and a base produces unsaturated cinacalcet base. Catalytic
hydrogenation using palladium carbon and hydrogen pressure reduced
the unsaturated cinacalcet base to cinacalcet base according to the
following scheme (7).
F3C Br F3C
HN
HN
F3C
HN
+
Hack coupling
reaction
K2CO3,
NMP
Pd / C
Pd / C,
H2,
Ethanol
Catalytic
Hydrogenation
Unsaturated cinacalcet base
Cinacalcet base
Allyl amin3-bromotrifluoro toluene e
9
Scheme (7)
As discussed earlier about shortcomings of Hack coupling reaction and
use of palladium carbon for catalytic hydrogenation apply same here to
make process expensive and lesser viable for industrial scale up.
US2009/0137837 discloses processes for preparation of cinacalcet from
allylic amination route as disclosed in scheme (8).
F3C R1
R1
+ R O
O
O R1
O
F3C
O R1
O
H2N
F3C
HN
F3C
HN
Catalyst
Pd-phophine complex
Cinacalcet
Catalytic
hydrogenation
F3C
O F3C
OR2
H2N
(R 2 =H, acetate, boc)
Vinyl magneshium
chloride
Pd-phophine complex
Scheme (8)
This process is not viable on industrial scale as expensive reagents like
palladium metal catalyst and chemistry using vinyl magnesium chloride
is not efficient in yield required for commercialization of the process.
10
Another process disclosed in said US2009/0137837 patent facilitates CO
to C-N rearrangement using metal alkoxide in first step and in second
step palladium catalyst facilitates rearrangement to give unsaturated
amine according to Scheme (9).
F3C
HN
F3C
Metal AlkoxidOR2 e
F3C
O
O
HN
Pd
Catalyst
HN F3C
Catalytic
hydrogenation
Cinacalcet
Scheme (9)
Another route discussed peptide coupling methods according to scheme
(10) Trifluoro acid intermediate and amine naphthalene coupled by
typical peptide coupling reagent like HBTU, HATU, TBTU, CDI.
F3C
HN
F3C
HN
F3C
Cinacalcet
Catalytic
hydrogenation
OH
O
H2N
Peptide coupling
reagent
11
Scheme (10)
But peptide coupling reagents are much expensive and it's tedious
isolation method difficult to incorporate to large scale production.
Yet Another route (Scheme (11)) involve hydroboration step for the
preparation of cinacalcet from 1-(3-trifluoromethylphenyl)-2-propene
admixing the allylbenzene with borane. Next N-chloro-1(1-
naphthyl)ethylamine is added to the mixture to form cinacalcet.
F3C
HN
F3C
Cinacalcet
HN
1) BH3
Cl
2)
Scheme (11)
But hydroboration reagents are expensive and process by using it is
lesser viable to industrial product.
US2011/0105799A1 discloses the process to prepare cinaclacet. In
second step of this process oxalate salt has been prepared to get higher
yield as per scheme (12).
12
F3C
O
Methanol
H2N
F3C
N
F3C
N
NaBH4,
NaOH Oxalic acid
F3C
N Pd-C, H2
Cinacalcet
Scheme (12)
Here oxalate salt is prepared to obtained higher yield but on expense of
adding one more intermediate. This route also prepared cinacalcet by
catalytic hydrogenation using expensive palladium catalyst, which is not
viable.
US2008/0319229A1 disclosed the process for the preparation of
cinacalcet and it's salt as per following scheme (13).
F3C Br
Pd-C, PPh3
H2N
F3C
F3C
HN
Cinacalcet
OH
OH
MsCl
TEA F3C
OMs
F3C
HN
Pd-C
Isopropanol
K2CO3
Scheme (13)
13
3-bromobenzotrifluoride and propargyl alcohol used to prepare alcohol
by using palladium chloride and triphenylphophine. Next it is reacted
with methanesulfonyl chloride to prepare a mestyl of the alcohol. Further
it condensed with naphthylethylamine to produce unsaturated cinacalcet
which further reduced by palladium carbon and isopropanol. Process
described in Scheme (13) has multiple stage which compromising yield
and use of expensive palladium carbon decreases commercial viability of
the process.
US2011/0207965A1 discloses novel mannich base iodide intermediate,
which is reacted with naphthylehylamine in presence of potassium
carbonate in acetonitrile, obtained carbonyl intermediate was reduced by
zinc powder and methanol, according to scheme (14).
H2N
F3C
F3C
HN
Cinacalcet
K2CO3
O
N
F3C
O
HN
Zn
Methanol / Water
Scheme (14)
The process described in scheme (14) have only two steps to prepare
cinacalcet but involve zinc and yield is less.
14
US2011/0319663 discloses the procedure to prepare cinacalcet and it's
salt by starting from naphthylethylamine and benzaldehyde to prepare
mannich base which reacted to bromo derivative of trifluoro methyl
propylbenzene in NMP according to scheme (15)
H2N
F3C
HN
Cinacalcet
+
O
25-30oC
N
F3C
Br NMP
Scheme (15)
Process compromising on yield and particularly second step is tedious.
US2012/0053362A1 discloses the process for preparation of cinacalcet
and it's salt scheme (16). Disclosed preparation of 3-trifluoromethyl
cinnamic acid reduced to give propionic acid derivative and it is reduced
to alcohol by BDMS in THF. The alcohol intermediate reacted with
methansulfonyl chloride to give mesityl derivative which coupled with
naphthyl methyl amine to produce cinacalcet.
15
F3C
HN
Cinacalcet
Pd - C
F3C
OH
O
F3C
OH
O
BDMS / THF
F3C
OH
CH3SO2Cl
F3C
OMs
H2N
Scheme (16)
In this process in the second step BDMS used to produce alcohol. The
reagent is expensive and also generates by products.
PCT publication WO2012/007954 Scheme (17) disclosed a process for
the cinacalcet formula (1) hydrochloride from 3-[3-
(trifluoromethyl)phenyl]-propionaldehyde and (R)-1-(1-
napthyl)ethylamine in tetrahydrofuran with presence of titanium(IV)
isopropoxide. The intermediate was reduced with sodium
cyanoborohydride in methanol and separated the cinacalcet base formula
(1). cinacalcet hydrochloride prepared using hydrochloric acid and
diisopropyl ether. 3-[3-(trifluoromethyl)phenyl]-propionaldehyde prepared
by reacting 3-(trifluoromethyl)cinnamic methyl easter with DIBAL.
16
F3C
HN
Cinacalcet
Pd - C
F3C
OH
O
F3C
O
O
DIBAL F3C
O
H2N
Methanol / H+
1) Ti(O-iPr)4
2) NaBH4
Scheme (17)
According to Scheme (17) the palladium catalyst, DIBAL and titanium
tetra isopropoxide is used. DIBAL is not safe for handling at commercial
scale.
There is therefore the need to provide an improved process for
preparation of cinacalcet or a salt thereof of significantly high yield and
purity, whereby the said cinacalcet or a salt thereof is prepared from low
cost raw materials and which is least toxic and involves inexpensive
reagents.
DISADVANTAGES OF PRIOR ART
The above mentioned inventions suffer from at least one of the following
problems:
- Most of them do not provide high purity of cinacalcet hydrochloride.
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- Most of them do not provide high yield of cinacalcet hydrochloride.
- Most of them use high cost raw materials.
- Most of them involve highly toxic reagents.
- Most of them involve high cost reagents.
- Most of them are highly expensive making the process non viable for
the industries.
OBJECTS OF THE INVENTION:
The main object of the invention is to provide an improved process for
preparation of cinacalcet hydrochloride with high yield and purity.
Another object of the invention is to provide an improved process for
preparation of cinacalcet hydrochloride without isolation of
intermediates.
Yet another object of the invention is to provide an improved process for
preparation of cinacalcet hydrochloride which involves use of minimum
solvent.
Further object of the invention is to provide an improved process for
preparation of cinacalcet hydrochloride which avoids use of hazardous
and expensive reagents.
Further object of the invention is to provide an improved process for
preparation of cinacalcet hydrochloride which is environmentally
friendly.
18
Further object of the invention is to provide an improved process for
preparation of cinacalcet hydrochloride which uses economic raw
material.
Further object of the invention is to provide an improved process for
preparation of cinacalcet hydrochloride which is economic.
DESCRIPTION OF INVENTION
The main embodiment of the proposed invention is to provide an
improved one-pot process for the preparation of cinacalcet hydrochloride
or salt thereof of significantly high purity. Further the present invention
relates to a process wherein the intermediates formed in the synthesis
are not isolated and cinacalcet hydrochloride or salt thereof is obtained
directly.
F3C
HN
HCl
Formula (1)
F3C
O
Formula (2)
H2N
Formula (3)
An improved process for the preparation of cinacalcet hydrochloride or
salt thereof mainly comprises of the following steps:
19
Step-1: Reaction of 3-[3-(Trifluoromethyl) phenyl] propionaldehyde of
formula (2) and (R)-1-(1-napthyl) ethylamine of formula (3) in presence of
base and organic solvent to form an imine and further in-situ;
Step-2: reduction of imine by metal reducing agent to obtain cinacalcet
base;
Step-3: formation of acid addition salt by adding acids without isolating
cinacalcet base and
Step-4: purification of cinacalcet hydrochloride.
The said base in the proposed invention is selected from sodium
carbonate, potassium carbonate, cesium carbonate sodium bicarbonate,
potassium bicarbonate or mixture thereof.
Further, in the proposed invention, for imine formation preferably
carbonates are used and most preferably potassium carbonate is used.
Further, the solvents which are used for the reaction, are organic
solvents comprises of chlorinated hydrocarbon, hydrocarbon, alcohol,
amides and nitriles or mixture thereof. The said chlorinated
hydrocarbons are selected from the group consisting of dichloromethane,
dichloroethane, monochlorobenzene or dichloro benzene. The said
hydrocarbons which are used are toluene or xylene. The said alcohols
used are from the group of methanol, ethanol or n-propanol. The said
amides are selected from the group of dimethyl formamide and dimethyl
acetamide. The said nitriles are selected from the group consisting of
acetonitrile, propinonitrile. The solvent used for imine formation is
preferably dichloromethane or dichlorethane.
20
Further, the temperature at which the reaction is carried out varies from
100c to 500C whereby the preferable temperature is in range of 25 to 40
degree and most preferably temperature is in range of 32 to 370c. The
imine intermediate thus formed is in-situ reduced by adding a reducing
agent as per process step-2.
The said reducing agent used for the reaction is selected from the group
of sodium triacetoxy borohydride, sodium borohydride, potassium
borohydride or sodium cyanoborohydride, most preferably sodium
borohydride. The reducing agent is to be added slowly in reaction mass
or it is dissolved in a suitable solvent and then gradually charged into
reaction mass. The solvent which is be used for dissolution are
methanol, ethanol, n-propanol or water. A mixture of organic solvent
with water can also be used. For addition of sodium borohydride, the
reaction mass is cooled slightly and then added. On the said addition,
temperature is raised slightly, preferably 20-25 0c is maintained till
completion of reduction, which is monitored by GC or HPLC. On
completion of reaction the excess sodium borohydride is removed by
adding water in the mass and removing the aqueous layer. The
cinacalcet base is formed after reduction remains in organic layer and
further it is converted into acidic salt as per process step-3.
The acids, which are used are from the group of inorganic and organic
acid. The inorganic acids are hydrochloric acid, sulphuric acid and
organic acids used are tartaric acid, oxalic acid, preferably concentrated
hydrochloric acid is used. The cinacalcet hydrochloride thus formed by
using concentrated hydrochloric acid is obtained by concentrating the
solvent used. The solvent used is distilled at atmospheric pressure or
under vacuum. To the cinacalcet hydrochloride thus obtained methyl terbutyl
ether is added and the mixture is heated to 500C and kept for some
21
time. It is cooled to 20-250c and filtered to obtain cinacalcet
hydrochloride.
The cinacalcet hydrochloride is further purified as per process step-4 to
obtain highly pure material, which meets the criteria of ICH quality
where individual impurity is below 0.1%. The solvents, which are used
for the purification of cinacalcet hydrochloride comprises of the group of
alcohols, nitrile, ethers, water and mixture thereof. The alcohols used are
from methanol, ethanol, n-propanol, isopropanol, isobutanol, or nbutanol,
the nitrile used are acetonitrile or pripionitrile, ethers is selected
from diethyl ether, isopropyl ether, methyl ter butyl ether and water.
Preferably solvent used is methanol and most preferably a mixture of
methanol and water is used for purification. The cinacalcet hydrochloride
thus obtained has a purity which qualifies in the criteria of ICH guideline
wherein maximum individual impurity is less than 0.1%.
Dated this 4th day of June, 2013
________________________
GOPI J. TRIVEDI (Ms)
Patent Attorney
At Y. J. Trivedi & Co.
(Authorized Agent of the Applicant)
To,
The Controller of Patents,
Patent Office,
Mumbai