Specification
2 PROCESSES FOR THE PREPARATION OF CINACALCET
Field of the Invention
The present invention provides processes and intermediates for preparing cinacalcet base and pharmaceutically acceptable sahs thereof.
Background of the Invention
Cinacalcet, chemically designated as N-[l-(R)-(-)-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-l-aminopropane hydrochloride is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. It is disclosed in U.S. Patent Nos. 6,211,244; 6,011,068; 6,313,146 and 6,031,003.
Sensipar® (cinacalcet) is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
U.S. Patent Nos. 6,011,068; 6,211,244 and 6,313,146 describe cinacalcet base and its pharmaceutically acceptable salts but do not provide any example for its preparation.
Several processes have been reported for the preparation of the cinacalcet base, its derivatives and pharmaceutically acceptable salts thereof
Drugs (2002), 27(9), 831-836 discloses a synthetic scheme for preparing cinacalcet which is also disclosed as a general procedure in U.S. Patent No. 6,211,244. The process involves reaction of 3-[3-(trifluoromethyl)phenyl]propionaldehyde prepared by Swem oxidation of the corresponding alcohol with (R)-l-(l-naphthyl)ethylamine in the presence of titanium isopropoxide to give imine which upon reduction gives cinacalcet base. However, the use of highly inflammable and toxic titanium isopropoxide in this process limits its practicability on the industrial scale.
In accordance with U.S. Patent No 6,211,244, cinacalcet may also be prepared by reacting 1-acetylnaphthalene with 3-3-[-(trifluoromethyl)phenyl]propylamine in the presence of titanium isopropoxide, followed by reduction using sodium cyanoborohydride and resolution of the resulting recemic cinacalcet base by chiral liquid chromatography. U.S. Patent No. 6,211,244 also discloses reaction of 3-trichlorocinnamoylnitrile and (R)-l-naphthylethylamine in the presence of diisobutylaluminium hydride (DIBAL) followed by the reduction of the imine intermediate to produce cinacalcet. Diisobutylaluminium hydride is inflammable and not ideal for the commercial scale up.
The process outlined in U.S. Patent No. 7,393,967 involves combining l-bromo-3-(trifluoromethyl)benzene with N-[(lR)-l-(naphthalen-l-yl)ethyl]prop-2-en-l-amine in the presence
3 of a catalyst and a base. However, the reaction is carried at a high temperature for about 3 to 24 hours.
The subsequent U.S. PubHcation No. 2009/0137837 describes the process for the preparation of cinacalcet involving allylic amination of l-[3-(3-trifluoromethyl)phenyl]propene with (R)-l-naphthylethylamine in the presence of transition metal catalyst followed by the reduction. This process involves the use of expensive palladium and platinum catalyst for the condensation and column chromatography for the isolation of intermediates.
Thus there is a need in the art for an improved process for the preparation of cinacalcet which employs less expensive, easily available and envirormient friendly reagents.
Summarv of the Invention
The present invention provides processes and intermediates for preparing cinacalcet base of Formula I and pharmaceutically acceptable salts thereof, employing non-expensive, easily available reagents.
Formula I
The first aspect of the present invention provides a process for preparing cinacalcet base of Formula I or a pharmaceutically acceptable salt thereof. The process comprises the steps of
a) reacting 1,3-dichloropropene of Formula II with (R)-1 -(1 -naphthyl)ethylamine of Formula III
H2N^J<;yJL
ciHc^ CH2C1 T T il
^•^^ CH3 ^^s^/'^
Formula II Formula III
to give a compound of Formula IV; and
CIHC=HC NH Jkx JL
CH3 k^ Formula IV
6. A process for preparing cinacalcet base of Formula I and its pharmaceutically acceptable
salts, comprising the steps of
a) converting 3-(trifluoromethyI)benzaldehyde to l-[3-(trifluoromethyl)phenyl]prop-2-en-
l-ol (Formula VII);
ff^^ CH2
OH Formula VII
b) converting l-[3-(trifluoromethyl)phenyl]prop-2-en-l-ol to a compound of Formula IX;
L Formula IX
wherein 'L' is a leaving group;
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c) reacting the compound of Formula IX with (R)-l-(l-naphthyl)ethylamine in the
presence of a base to give a compound of Formula VI or pharmaceutically acceptable
salts thereof;
CH3 L J
Formula VI
d) reducing the compound of Formula VI or pharmaceutically acceptable salts thereof to
cinacalcet base or pharmaceutically acceptable salt thereof.
7. A process for preparing cinacalcet base of Formula I and pharmaceutically acceptable salts
thereof, comprising the steps of
a) converting 3-[3-(trifluoromethyl)phenyl]prop-2-en-l-ol (Formula VIII)
Formula VIII
to a compound of Formula X
Formula X
wherein, 'L' is a leaving group; and
b) converting the compound of Formula X to cinacalcet base or pharmaceutically
acceptable salts thereof.
8. A process for preparing cinacalcet base of Formula I and its pharmaceutically acceptable
salts, comprising the steps of
a) converting 3 -(trifluoromethyl)benzaldehyde to 1 - [3 -(trifluoromethyl)phenyl]prop-2-en-
l-ol (Formula VII);
OH Fomnula VII
b) isomerising l-[3-(trifluoromethyl)phenyl]prop-2-en-l-ol to 3-[3-
(trifluoromethyl)phenyl]prop-2-en-l-ol (Formula VIII);
F3cXX^^°" FomnulaVIII
c) converting 3-[3-(trifluoromethyl)phenyl]prop-2-en-l-ol (Formula VIII) to a compound
of Formula X;
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Formula X
wherein 'L' is a leaving group;
d) reacting the compound of Formula X with (R)-l-(l-naphthyl)ethylamine in the presence
of a base to give unsaturated compound of Formula VI or pharmaceutically acceptable
salts thereof;
A A
T T il
CH3 ksJ
Formula VI
e) reducing the compound of Formula VI or pharmaceutically acceptable salts thereof to
cinacalcet base or pharmaceutically acceptable salts thereof.
9. A process for preparing cinacalcet, comprising the steps of
a) reducing the salts of the compound of Formula VI;
A A
T T il
CH3 k^
Formula VI
b) isolating cinacalcet in a solvent.
The process according to claim 9, wherein the salts of compound of Formula VI is selected from a group consisting of hydrochloride, hydrobromide, hydroiodide, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, fiimarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate or camphor sulfonate.
The process according to claim 10, wherein the salt is selected from hydrochloride, hydrobromide, ftimarate or citrate.
The process according to claim 9, wherein cinacalcet is isolated in a solvent selected from a group consisiting of water, acetone, diethylether, tert-butylethylether, n-pentane, n-hexane, hexanes, ethylacetate, isopropylacetate, toluene, methyl-t-butyl ether or cyclohexane.
A process for preparation of cinacalcet base of Formula I and its pharmaceutically acceptable salts comprising the steps of:
a) providing salt of Formula VI;
b) converting salt of Formula VI to free base;
reducing the free base to cinacalcet free base;
converting cinacalcet free base to cinacalcet.
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The process according to claiml3, wherein the salts of compound of Formula VI is selected from a group consisting of hydrochloride, hydrobromide, hydroiodide, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate or camphor sulfonate
The process according to claim 13, wherein the salt is selected from hydrochloride, hydrobromide, fumarate or citrate.
The process according to claims 9 and 13, wherein reduction involves hydrogenation using hydrogen source in the presence of a catalyst or a reducing agent.
The process according to claim 16, wherein reduction involves hydrogenation using metal catalysts or reducing agents.
The process according to claim 17, wherein reduction involves hydrogenation using metal catalysts selected from palladium, platinum or Raney nickel.
The process according to claim 17, wherein reduction involves hydrogenation using reducing agents selected from sodium hydride, sodium borohydride, lithium alluminium hydride, Diisobutylaluminum hydride, or Vitride®.
Pharmaceutically acceptable salts of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine of Formula VI in a solid state form
A A
CH3 ^^ J Formula VI
Pharmaceutically acceptable salts according to claim 20 are selected from hydrochloride, hydrobromide, sulfate, fiimarate, acetate, lactate, malonate, citrate, quinate, succinate, oxalate, maleate, tartarate or camphor sulfonate.
Hydrobromide sah of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine of Formula VI.
Hydrobromide salt of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine of Formula VI, having characteristics d-spacing (A) values selected from 6.74, 6.20, 5.33, 4.50, 4.30, 3.96, 3.38 or 3.28.
Hydrochloride sah of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine of Formula VI, having characteristics d-spacing (A) values selected from 6.36, 5.46, 4.75, 4.66, 4.41, 4.27 or 3.67.
Hydrochloride salt of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine according to claim 24, having one or more of following characteristics:
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XRD pattern substantially as depicted in Figure 1;
DSC substantially the same pattern as depicted in Figure 2, wherein DSC shows an endothermic peak at 199.0rC;
TGA substantially the same as depicted in Figure 3.
Fumarate salt of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine.
Fumarate salt of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine, having one or more of following characteristics:
XRD pattern substantially the same as depicted in Figure 5;
DSC having substantially the same pattern as depicted in Figure 6, wherein DSC shows an endothermic peak at 166.79°C;
TGA having substantially the same pattern as depicted in Figure 7.
Citrate salt of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine.
Citrate saU of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine having one or more of following characteristics:
XRD pattern substantially the same as depicted in Figure 8;
DSC having substantially the same pattern as depicted in Figure 9, wherein DSC shows an endothermic peak at 130.88°C;
TGA having substantially the same pattern as depicted in Figure 10.
Pure cinacalcet, wherein cinacalcet has purity more than 98.0 % when determined by HPLC.
Pure cinacalcet, wherein cinacalcet has purity more than 99.0% when determined by HPLC.
Pure cinacalcet, wherein cinacalcet has purity more than 99.5% when determined by HPLC.
Cinacalcet, wherein the compound of Formula VI is present in an amount less than 0.10% when determined by HPLC.
Cinacalcet, wherein the compound of Formula VI is present in an amount less than 0.05% when determined by HPLC.
Cinacalcet, wherein the compound of Formula VI is not detectable when determined by HPLC.
Cinacalcet free of an impurity at RRT 1.724 when determined by HPLC.
Pharmaceutical composition comprising one or more salts of N-[(lR)-l-(naphthalen-l-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-l-amine and pharmaceutically acceptable excipients.
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A method for treating a subject in need of an inorganic ion receptor-modulating compound wherein, the ion receptor-modulating compound is selected from one or more salts of N-[(1R)-1 -(naphthalen-1 -yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1 -amine.
The processes for the preparation of cinacalcet of Formula I or salts thereof as described herein with reference to the examples provided herein.
Dated this the 9™ day of April, 2012.
For Ranbaxy Laboratories Limited
(Dr. Santanu De) Associate Director - Intellectual Property