FORM 2
THE PATENT ACT 1970
(39 of 1970) &
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARING CINACALCET HYDROCHLORIDE
2. APPLICANT (S)
(a) NAME: Mecleods Pharmaceuticals Limited
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 3rd Floor, Church Road, Near Leela Hotel, Andheri (East),
Mumbai - 400 059, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention.

Technical field
This invention relates to a process for preparing Cinacalcet hydrochloride, (R)-a-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthalene methane amine hydrochloride.
Background and prior art
Cinacalcet Hydrochloride is a common name of the chemically known substance (R)-a-
methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphtahlene methane amine
hydrochloride),having a CAS number of 364782-34-3,a formula of C22H22F3N.HCl and represented by the following structure.

Cinacalcet hydrochloride is marketed as Sensipar ™ and is the first drug in a class of compounds known as Calcimimetics. Calcimimetics are orally active molecules that decrease the secretion of parathyroid hormone by activating calcium receptors. These class of compounds are used to treat hyper para thyroidism, a condition characterized by the over secretion of parathyroid hormone. Cinacalcet hydrochloride is approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.
US patent No 6,011,068 discloses calcium receptor-active molecules, such as those having the general structure of Cinacalcet. As per US patent N06, 211,244 ('244 patent).Cinacalcet may be produced by reacting 1-acetyl naphthalene with
3-[3(trifluoromethyl)phenyl]propyl amine in the presence of titanium isopropoxide to produce an imine which on treatment with methanolic sodium borohydride and resolution of the racemic Cinacalcet base by chiral liquid chromatography(Scheme I).
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The desired Cinacalcet enantiomer may be produced by reacting ( R )-l-(l-naphthyl)ethyl amine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium isopropoxide to produce the imine followed by treatment with ethanolic sodium cyano borohydride as disclosed in '244 patent and Drugs of the Future(2002)27(9):831(Scheme
II).

Another process in '244 patent describes treating 3-trifluromethylcinnamonitrile with Diisobutyl aluminium hydride, followed by treating the intermediate aluminium-imine complex with (R)-l-(l -naphthyl) ethyl amine, and reducing the resultant imine with ethanolic Sodium cyanoborohydride(Scheme III).
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The above three reported processes require reagents such as Titanium isopropoxide, DIBAL-H and Sodium cyano borohydride. All the above reagents were toxic, flammable and not environmental friendly, making the process difficult to apply on industrial scale.
The synthesis 3-[3-(trifluoromethyl) phenyl]propionaldehyde is disclosed in the references and notes section as entry no 12 of Tetrahedron letters(2004)45,8355 (Scheme IV).

The process for the synthesis of aldehyde involves the reduction of double bond of the cinnamic acid derivative followed by reduction of acid to alcohol, which was subjected to Swern oxidation to get the aldehyde. The Swern-oxidation involves the use of reagents such as Oxalyl Chloride and DMSO, which are not environmental friendly and does not result in high yield, making the process uneconomical on industrial scale.
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WO2006/125026 discloses another synthetic procedure for preparation of Cinacalcet. This procedure involves the Heck coupling of l-Bromo-3-trifluoromethyl benzene with acrolein dialkyl acetal to get a mixture of unsaturated acetal (I) and saturated ester (II) .The mixture of compounds was hydrolyzed to get a mixture of unsaturated aldehyde(III) and saturated ester (II). When the mixture of unsaturated aldehyde (III) and saturated ester (II) was subjected for double bond reduction it furnished a mixture of saturated aldehyde(IV)and saturated ester (II). Similarly when the mixture of unsaturated aldehyde (IV) and saturated ester(II) was subjected for carbonyl moiety reduction it furnished a mixture of unsaturated alcohol(V) and saturated alcohol(VI).The mixture of saturated aldehyde(IV) and saturated ester(II) was subjected to reduction of carbonyl moiety and the mixture of unsaturated alcohol(V) and saturated alcohol(VI)were subjected to reduction of double bond to get the saturated alcohol(VI) (Scheme V).


Scheme V
The Heck reaction involves palladium catalyst which is a precious metal catalyst. The condensation of l-Bromo-3-trifluoromethyl benzene with acrolein dialkyl acetal gave two products.The formations of multiple products during each conversion to get the alcohol (VI) makes the process unattractive from synthetic point of view.
WO2006/125026 discloses another strategy for the preparation of Cinacalcet.This procedure involves the Heck coupling of l-Bromo-3-trifluoromethyl benzene with Ethyl acrylate to get the unsaturated ester, which was subjected to reduction of double bond and reduction of carbonyl moiety to get the saturated alcohol, which was converted to a leaving group and condensed with (R)-l-(l-naphthyl) ethyl amine to get Cinacalcet base (Scheme VI)

The synthesis reported above (Scheme VI) also involves a Heck coupling reaction, which involves the use of palladium catalyst.
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Disclosure of the invention:
The present invention provides a process for the synthesis of Cinacalcet base as illustrated in Scheme VII comprising:
a. condensing 3-trifluoromethyl benzaldehyde (I) with malonic acid(VII) to obtain the
unsaturated acid (VIII);
b. reducing the unsaturated acid to obtain a saturated acid (IX);
c. converting the acid to acid chloride followed by condensing with (R)-l-(l-naphthyl) ethyl
amine to get the amide(X); and
d. reducing the amide to obtain cinacalcet followed by converting into hydrochloride salt.

Examples:
Example 1:
Preparation of 3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (VIII)
3-Trifluoromethylbenzaldehyde (50.0 gm, 0.287 moles), malonic acid (32.90 gm, 0.315 moles) and piperidine (3.66 gm, 0.043 moles) in dry pyridine (80 ml) was heated at 110-115 °C for 4-5 h. The progress of the reaction was monitored by TLC. On completion of the reaction, the mixture was cooled to room temperature and chilled water (400 ml, 0-5 °C) was added to the reaction mass and stirred for 1 hour. pH of the reaction mass was adjusted to 2-3
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with 2 N HCl solution (200 ml) at 5 - 10 °C and stirred for 1 hour. The resulting solid was filtered, washed with chilled water (400 ml, 0-5°C) and dried at 50 - 55 °C to get title compound. (45 gm, 72.52 %).
Melting point: 131 - 133°C.
IR(KBr) (vmax:cm-1): 1689.53, 1631.67, 1442.66, 1261.36, 1176.50, 1072.35, 937.34, 871.76,
806.19,694.33,655.75.
'H NMR (CDCl3) (dppm): 7.53 - 7.84 (5H, m), 6.53 (1H, d).
MS(m/z):215[M-l]
Example 2:
Preparation of 3-[3-(trifluoromethyl) phenyl]-2-propanoic acid (IX)
3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (50 gm, 0.231 moles), methanol (250 mL)
and 10 % palladium on carbon (2.5 gm, 5%) was autoclaved for 2.5-3.0 h under hydrogen
pressure of 4 kg at 20-25 °C. The progress of the reaction was monitored by TLC. Upon
completion of reaction, the reaction solution was filtered through celite and the reaction
mixture was distilled under reduced pressure at 40 - 45 °C to give title compound. (48 gm,
95.20%).
Melting point: 30 - 35 °C.
IR (KBr) (vmax cm-1): 2966.62, 2947.33, 2889.46, 1712.85, 1454.38, 1330.93, 1168.90,
1134.18,1076.32,802.41,702.11.
'H NMR (CDCI3) (5 ppm): 10.59 (1H, bs), 7.39 - 7.47 (4H, m), 3.03 (1H, t), 2.68 (1H, m).
MS(m/z):217[M-l]
Example 3:
Preparation of N-[l-(R)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l-
propanamide(X)
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Thionyl chloride (6.69 ml, 0.0917 moles) was added dropwise to a solution of 3-[3-(trifluoromethyl) phenyl]-2-propanoic acid (10 gm, 0.045 moles), dimethylformamide (0.5 ml) and dry toluene (100 ml) at 25 - 30 °C under nitrogen atmosphere. The reaction mixture was heated to 70 - 75 °C for 2.0 h. After 2.0 h the toluene was distilled under reduced pressure at 50 - 55 °C. Fresh toluene (100 mL) was further added to reaction mixture to get clear solution. This solution was added dropwise to a solution of (1R)-1(1-naphthyl)ethane amine (4.88 gm, 0.0285 moles), triethylamine (11.53 gm, 0.114 moles) in methylene chloride (200 ml) at 0 - 5 °C for 1.5 - 2.0 h under nitrogen atmosphere. After completion of the reaction (by TLC), water (50 ml) was added in the reaction mixture and the layers were separated, the organic layer was washed again with water (50 ml). The organic layer was evaporated under reduced pressure to get a crude solid, which was then dissolved in a mixture of hexane (25 ml) and ethyl acetate (30 ml) at reflux and the cooled to 0 - 5 °C to get solids which was filtered and dried at 50-55°C to get the title compound (10 gm, 70.87 %).
Melting point: 108-111°C.
IR (KBr) (vmax cm-1): 3298.38, 3082.35, 2970.48, 2357.09, 1643.41, 1554.68, 1450.52,
1330.93, 1122.61, 1072.48,798.56,775.41,705.97.
'H NMR (CDCl3-DMSO-d6) (d ppm): 7.26 - 8.03 (11H, m), 5.91 (1H, m), 5.58 (1H, bd),
3.03 (2H, m), 2.46 (2H, m), 1.60 (3H, d).
MS(m/z):372[M+l].
Example 4:
Preparation of (R)-a-methyl-N- [3-[3-(trifluoromethyl) phenyl] propyl]-1 - naphthalene
methane amine hydrochloride.
To a suspension of N-[l-(R)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l-propanamide (50 gm, 0.134 moles) and NaBFH4 (50 gm, 1.313 moles) in dry THF (600 ml) under nitrogen atmosphere was added a solution of iodine (167.5 gm, 0.66 moles) in dry THF (800 mL) at 0 - 5 °C for 2.5 hours. The reaction mixture was then brought to room
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temperature and then refluxed (70 - 75 °C) for 4.0 h. The reaction mass was cooled to 0-5°C and the excess borohydride destroyed by careful addition of 3 N HC1 (150 ml). The reaction mixture was basified using 3 N NaOH (225 ml). The organic layer was separated and the aqueous layer was extracted with methylene chloride (2 x 100 ml). The combined organic extracts were washed with water (100 ml) and dried over Na2SO4. The organic layer was evaporated to dryness under vacuum at 40 - 45 °C to get a residue, which was dissolved in hexane (300 ml) and 10 % HC1 solution (300 mL) was added at room temperature and stirred for 1 h. The solids separated were filtered and washed with hexane (5 x 25 mL) and dried to get the crude product. The crude product was dissolved in acetonitrile (450 mL) at reflux temperature and then cooled to room temperature, filtered the solids and dried at 50 - 55 °C for 8 h to get Cinacalcet HC1 (51.0 gm, 96.22 %).
Melting point: 180-184°C.
IR (KBr) (vmax cm-1) 3437.26, 3363.97, 2962.76, 2796.88, 2750.58, 2712.01, 2511.40,
1585.54, 1450.52, 1327.07, 1168.90, 1130.32, 1072.46, 798.56, 775.41, 702.11.
'H NMR (CDCl3-DMSO-d6) (d ppm): 10.62 (1H, bs), 10.07 (1H, bs), 7.16 - 8.5 (11H, m),
5.19 (1H, q), 2.75 (2H, t), 2.52 (2H, m), 2.28 (2H, m), 1.98 (3H, d).
MS(m/z):358[M+l].
Dated this 26th day of March 2007
Dr. P. Aruna Sree Agent for the Applicant
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