FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION (SECTION 10)
IMPROVED PROCESS FOR PREPARATION OF CINACALCET INTERMEDIATES
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN,
PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI (WEST), MUMBAI - 400102,
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR PREPARATION OF CINACALCET INTERMEDIATES
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved process for preparing compound, 3-(3-trifluoromethylphenyl) propanol, represented as compound II, which is a key intermediate for synthesis of cinacalcet, its salts and/ or solvates

BACKGROUND OF THE INVENTION
Cinacalcet hydrochloride has the chemical name, N-(l-(R)-(-)-l-napthyl)ethyl)-3-[3-trifiuoromethylphenyl]-l-aminopropane hydrochloride with an empirical formula of C22H22F3N.HCI, molecular weight 393.9 and a structural formula (I),

Cinacalcet hydrochloride is a commercially marketed pharmaceutically active substance known to be useful for treatment of hyperthyroidism and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer. It is marketed under the trade name of Sensipar® in United States and under the trade name Mimpara® in Europe.

US patent 6211244 (Bradford C.Van Wagenen et al, 1995) discloses cinacalcet and its pharmaceutically acceptable acid chloride addition salt, but does not provide any examples for the specific preparation of cinacalcet and/or cinacalcet hydrochloride. Drugs Of Future 2002, 27(9), 831-836 discloses the following synthetic route for preparation of cinacalcet hydrochloride according to Scheme 1.

According to Scheme 1, (lR)-l-(l-naphthyl)ethylamine is reacted with 3-[3-(trifluoromethyl)phenyl]propionaldehyde (III) by means of titanium tetraisopropoxide in

alcoholic solvents like ethanol to give the corresponding imine, which is then reduced to Cinacalcet base. This process gives low yields and less pure cinacalcet free base. Additionally, costly and toxic reagent like sodium cyanoborohydride is used for reduction to give cinacalcet base. The detailed description of this scheme is not disclosed in the publication.
The key intermediate, 3-[3-(trifluoromethyl) phenyljpropanal (compound III) can be prepared by oxidation of 3-[3-(trifluoromethyl) phenyl]propanol (compound II).
Tetrahedron Letters (2004), 45, 8355, footnote 12, describes the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde (III), wherein reduction of the double bond of the corresponding cinnamic acid derivative, followed by reduction with lithium aluminium hydride to give the corresponding alcohol, which is oxidized to 3-[3-(trifluoromethyl)phenyl]propionaldehyde (III) by Swern oxidation using oxalyl chloride, DMSO, triethylamine at -70 to -30 °C.

The disadvantage of this process includes low temperatures (-70 to -30°C) employed in the reaction, which are difficult to achieve on a large scale.
Several processes for preparing 3-[3-(trifluoromethyl) phenyl] propanol (compound II) have been described in the literature.

WO2006/125026 (Lifshitz-Liron, Revital et al, 2006) discloses a process for preparing compound II by Heck reaction of 3-Bromotrifluorobenzene with Acrolein diethylacetal/ ethyl acrylate, reduction of the double bond and the carbonyl moiety to get the corresponding alcohol (II) as described in Scheme 2.

The drawback of '026 is that the Heck reaction involves the use of costly palladium catalysts and employs high reaction temperatures. Also, the reduction of the corresponding unsaturated aldehyde/ester is carried out in two steps rather than a single step to get the product.

EPO194764 (Blade, Robert John et al, 1986) discloses a process in which 3-trifluoromethyl bromobenzene is reacted with prop-2-yne-l-ol using bis(triphenyl phosphine) palladium chloride and cuprous iodide in triethylamine followed by catalytic hydrogenation to give the corresponding alcohol(II) as shown in Scheme 3.

Scheme 3
The '764 process involves the use of very costly palladium-TPP catalysts for the coupling reaction and specialized equipment like autoclave for the subsequent reduction process. WO 2008/058236 (Padi, Pratap Reddy et al, 2007) discloses a process for the preparation of 3-(3-trifluoromethylphenyl)propan-l-ol from 3-[3-(trifluoromethyl)phenyl]propanoic acid and THF by reacting with lithium aluminum hydride, which is not only pyrophoric and expensive but also is difficult to handle on a large scale.(Scheme 4)

Thus, in light of the above cited prior art, there exists a need for the development of an improved, economical, scalable process which avoids the use hazardous and expensive agents for the synthesis of 3-[3-(trifluoromethyl)phenyl] propanol., an important intermediate of Cinacalcet.
OBJECT OF THE INVENTION
The object of the present invention is to provide an economical process for the synthesis
of 3-[3-(trifluoromethyl)phenyl]propanol.
Another object of the present invention is to provide a scalable process for the synthesis
of 3-[3-(trifluoromethyl)phenyl] propanol, a key intermediate in the preparation of
cinacalcet hydrochloride.
Another object of the present invention is to provide 3-[3-(trifluoromethyl)phenyl] propanol, an important reagent for cinacalcet with a good yield and purity.
SUMMARY OF THE INVENTION

comprising reduction of compound XVII
The present invention relates to a process for preparing 3-[3-(trifluoromethyl)phenyl] propanol (compound II)


with reducing agent, in presence of catalyst and a organic base, wherein R is methyl, ethyl, butyl.
According to further aspect of the present invention, there is provided a process for
preparing Cinacalcet and/or its pharmaceutically acceptable salts and/or solvates
comprising
a. oxidation of 3-[3-(trifiuoromethyl)phenyl] propanol (compound II)

in a solvent in the presence of a base to give 3-[(3-trifluoromethyl)phenyl]propanal (compound III);

b. reacting 3-[(3-trifluoromethyl)phenyl]propanal (compound III) with titanium tetraisopropoxide in a solvent and reverse addition to (lR)-l-(l-naphthyl)ethylamine at 0-5 °C in presence of reducing agent to provide Cinacalcet base;


c. reacting cinacalcet base with methyltert-butyl ether hydrochloride in presence of a solvent to give cinacalcet hydrochloride salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the manufacture of 3-[3-(trifluoromethyl)phenyl] propanol, a key intermediate for the manufacture of cinacalcet and/ or its salt or solvates.
The main aim of the present invention is to provide an improved, economical, scalable and shorter process for the manufacture of 3-[3-(trifiuoromethyl)phenyl] propanol, with high yields wherein the use of expensive catalysts such as palladium catalysts, lithium aluminium hydride, harsh reaction conditions and longer reaction times are avoided. Transition metals or their salts have found applications in many synthetic molecules. The transition metal and base in catalytic amount is used for the preparation of 3-[3-(trifluoromethyl)phenyl] propanol in the present invention.
An embodiment of the present invention relates to a process for the formation of 3-(3-trifluoromethyl)cinnamic acid (compound XVI) by 1) condensation of 3-(3-trifluoromethyl)benzaldehyde (compound XV) with malonic acid using catalytic piperidine in pyridine, further, 2) formation of ester of compound (XVII), wherein R is

alkyl group like methyl, ethyl, butyl and 3) reduction of compound (XVII) to 3-[3-(trifluoromethyl)phenyl] propanol (II) using catalytic cobaltous chloride-diisopropyl amine and sodium borohydride in tetrahydrofuran-methanol as solvent. The complete process is illustrated as given in Scheme 5.

The present invention describes a process with less number of steps wherein both the double bond and the ethyl ester side chain of the compound XVII are reduced in a single step avoiding first catalytic palladium based reduction of double bond and subsequent reduction of the saturated ester.
The present invention also highlights the use of catalytic transition metal and amine combination (CoCI2-DIPA) for this reduction in presence of reducing agent selected from alkali metal hydrides such as lithium aluminium hydride, sodium hydride or alkali metal borohydrides such as lithium borohydride, sodium borohydride, preferably easily

available, cheap sodium borohydride as a source of hydrogen to prepare the key intermediate, 3-(3-trifluoromethyl)propanol (compound II).
According to one embodiment of the present invention, the reduction is performed preferably using 1-10 mol% cobaltous chloride hexahydrate and 1-5 mole % diisopropylamine. The reducing agent, sodium borohydride, is used in the range of 4-8 equivalents, more preferably 4-5 equivalents.
The organic base used is selected from triethylamine, tributylamine, diisopropylethylamine,diisopropylamine, trimethylamine, preferably diisopropylamine. The reaction temperature during the reaction is maintained between 35-50° C, more preferably in the range of 35-40 ° C. The preferred solvent combination is a mixture of ether and alcohol. The ethers are selected from MTBE, DIPE, diethyl ether, tetrahydrofuran, preferably tetrahydrofuran and alcohols are selected from methanol, ethanol, isopropanol, preferably methanol. Methanol is added drop wise to the reaction mass containing a mixture of cobaltous chloride hexahydrate-diisopropyl amine and sodium borohydride at the desired temperature range. The reaction is generally carried out for a time of approximately 2-6 hours, more particularly in 3-4 hours. Compound II can be purified by distillation under vacuum.
Another embodiment of the invention includes the use of compound II for preparation of compound III, which is a key intermediate in the synthesis of cinacalcet and/or its pharmaceutically acceptable salts and/or solvates thereof, comprising oxidation of compound II at temperature range 0-25°C in presence of phosphorus pentoxide in solvent such as dichloromethane in presence of dimethylsulfoxide and base such as triethylamine,

diisopropylethylamine, diisopropyl amine, trimethylamine, DBU, DBN, preferably triethylamine.
Yet another embodiment of the present invention relates to preparation of cinacalcet base, wherein 3-[3-(trifluoromethyl)phenyl]propionaldehyde (III) in presence of Titanium tetraisopropoxide and ethereal solvents like tetrahydrofuran, diethylether, methyltertbutyl ether, diisopropyl ether; alcohols like ethanol, methanol, isopropyl alcohol, preferably THF as solvent gives an aldehyde-titaniumtetraisopropoxide complex. Subsequently reverse addition of this complex to the (lR)-l-(l-naphthyl)ethylamine is carried out at low temperature between 0-30° C, preferably 10-15°C. Further, cheap and easily available reducing agent such as sodium borohydride is added to this reaction mixture. The reverse addition of aldehyde-titaniumtetraisopropoxide complex to (1R)-1-(1-naphthyl)ethylamine results in excellent conversion and good yields (90-92%) of cinacalcet base. Purity by HPLC- 95%.
Cinacalcet base is further converted to its hydrochloride salt by reacting cinacalcet base with methyl tertbutyl ether hydrochloride in presence of a solvent such as cyclohexane.
The scheme of the complete process is represented in given Scheme 6:


Scheme 6
Having described the invention with reference to certain preferred embodiments, the other embodiments will become apparent to one skilled in the art from consideration of the specification.
Examples:
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.

Example I
Preparation of 3-[(3-Trifluoromethyl)phenyl]-2-propenoic acid
3-Trifluoromethylbenzaldehyde (100 gm, 0.574 moles), malonic acid (66 gm, 0.634
moles) and piperidine (7.32 gm, 0.086 moles) in dry pyridine were heated at 110-115 °C
for 4-5 hours. On completion of the reaction (monitored by TLC), the reaction mixture
was cooled to room temperature and was added to cold water (1.0 lit.) at 0-5 °C. The pH
of the reaction mixture was adjusted to 2-3 with 2N HC1 solution at 0-5 °C and stirred for
1 hour. The resulting solid was filtered, washed with 1.0 lit of cold water(cooled to 0-5
°C) and dried at 60-65 °C under vacuum to get the title compound (100 gm)
HPLC purity-99.0%
Melting Point-135-137 °C
IR- 2923,2850,1685,1627,1440,1220,1160,1070, 690, 555.
1H NMR - CDC13 (5 ppm): 6.51 (1H, d), 7.53(lH,t), 7.65 (lH,d), 7.71(1H, d),
7.8(2H,d), 11.68(lH,s)
MS(m/z)-217[m+l]
Example II:
Preparation of Ethyl 3-[(3-Trifluoromethyl) phenyl]-2-propenoate
3-[3-Trifluoromethyl phenyl]-2-propenoic acid 20 gm (0.0819 mol) and 100mL ethanol were refluxed at 75-80 °C. Sulphuric acid (2.0 gm) was added slowly to the reaction mixture and refluxed for 2-3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and water (500 mL) was added. The reaction mixture was stirred for 30 min. Ethyl acetate (500 mL) was charged to the

reaction mixture, the extract was washed with saturated sodium bicarbonate solution (500
mL) and further with water (500 mL). The solvent was then distilled out to get the
compound as oil (21 gm)
IR-3041,2984, 1715,1642,1307.68, 1202.09,1156.90
NMR-1.32(3H,t), 4.25(2H,q), 6.47(1H, d), 7.48(1H, t), 7.60(lH,d), 7.66-7.68(2H,m),
7.74(lH,s)
Example III:
Preparation of 3- [(3-Trifluoromethyl)phenyl] propanol
Ethyl 3-[3-(Trifluoromethyl)phenyl]-2-propenoate (5.0 gm, 0.0204 mol), dry THF (50 mL), cobaltous chloride hexahydrate (0.00102 gm, 5 mol%) and diisopropyl amine (0.00102 gm, 5 mol %) were stirred at room temperature for 20 min, heated to 40° C and then added sodium borohydride (3.098 gm, 0.0819 mol) to it. Methanol (20 mL) was added to the reaction mixture in 2-3 hours. After completion of the reaction (monitored by TLC) the reaction mass was cooled to 20 °C, 5% HC1 solution (50 mL) was added and stirred for 30 min. The reaction mass was extracted with ethyl acetate, the ethyl acetate layer was washed with 50 mL of water. The ethyl acetate layer was distilled off under vacuum to get the title compound as oil. (3.98 gm) Yield- 95%
IR-3337.94, 2941.87, 1957.98, 1897.24, 1721.46, 1614.77, 1597.13, 1492.7, 1450.7 NMR-1.68-1.75(2H, m), 2.7(2H,t, J=7.6 Hz), 3.40(2H, q, J=5.9 Hz), 4.5(1H, t, J=5.2 Hz), 7.5-7.53 (4H, m) GC purity- 92%

Example IV
Preparation of 3-[(3-Trifluoromethyl)phenyl]propanal
Phosphorous pentoxide (522 gm, 3.07 mol) taken in dichloromethane (2 L) was cooled to
-10°C under nitrogen atmosphere. Dimethyl sulphoxide (335.09 gm, 4.28 mol) in
dichloromethane (500 mL) was added over a period of 1 hour to the reaction mixture and
stirred for 30 min. 3-[3-Trifluoromethylphenyl] propanol (250 gm, 1.22 mol) in
dichloromethane(500 mL) was added to the reaction mixture at-10 to 0°C over a period
of 1-1.5 hours and stirred for 30 min. The temperature of the reaction mass was raised to
20-25 °C. The reaction mixture was stirred at this temperature for 15-20 min and again
cooled to 0°C. Triethylamine (558 gm, 5.51mol) was charged over a period of 2-3 hours
and stirred for 1 hour. After completion of the reaction (as monitored by TLC) water (4
lit.) was added and allowed the reaction temperature to reach 25-30°C. The organic layer
was separated, washed with water (2L) and solvent distilled out to get crude compound
(247 gm). GC Purity- 89.0 %
The crude aldehyde was purified by high vacuum distillation (3-5 torr) at 80-85°C to give
pure aldehyde (193 gm). GC Purity - 99.5%
1H NMR(CDC13) ; 2.81(2H, t, J= 7.5Hz), 3.0 (2H, t, J-7.5 Hz), 7.38-7.43(4H, m), 9.81
(1H, s).
Example V
Preparation of Cinacalcet free base
3-[3-(trifluoromethyl)phenyl]-2-propanal (5.0 gm, 0.0247 mol), dry tetrahydrofuran,
titanium isopropoxide (7.37gm, 0.0259 mol) were stirred under nitrogen atmosphere at

10-15 °C for 1 hour. This solution was added drop wise to a solution of (1R)-(1-napthyl)ethyl amine (4.23 gm, 0.0247 mol) at 0-5 °C over a period of 5 hours and stirred for 1 hour after complete addition. Sodium borohydride (1.403 gm, 0.0371 mol) was added lot wise over a period of 1 hour. After complete addition the reaction mixture was stirred for 12 hours at 25-30 °C. The reaction mixture was then quenched by drop wise addition of water (50 mL). The reaction mixture was then stirred for 15-20 min and to the reaction mixture was added celite (10 gm) and toluene (50 ml). The reaction mixture was stirred for 30 minutes, filtered and the organic phase was washed with water (50 mL). Dilute Hydrochloric acid (50 mL) was added to the organic phase and the reaction mixture was heated to 65-70 °C. The reaction mixture was maintained at this temperature for 1 hour and cooled to 25-30 °C. The organic phase was separated and washed with saturated sodium bicarbonate solution (100 ml). The organic phase was further washed with water (100 ml). The solvent was distilled out under vacuum to get crude cinacalcet free base (8.0 gm) as oil. HPLC purity-93% Mass (m/z)-M+l-358
Example VI
Preparation of Cinacalcet Hydrochloride
Cinacalcet free base (10 gm, 0.0208 mol) was dissolved in cyclohexane(25 mL) at room temperature. To this solution, was added methyltert-butyl ether hydrochloride (4%, 51 mL, 0.0558 mol) drop wise at room temperature and stirred for 4-5 hours. Methyl tert-bufyl ether (49 mL) was further added drop wise to the reaction mixture and stirred for

10-15 hours at room temperature. The white solid was filtered and washed with MTBE (20 mL). The solid was dried under vacuum at 45-50 °C for 10-12 hours to get crude cinacalcet hydrochloride (8.1 gm). The crude cinacalcet hydrochloride was recrystallised in isopropyl alcohol (55mL) to get pure cinacalcet hydrochloride (6.48 gm) HPLC purity 99.5%
1H NMR - 1.69(3H, d), 1.96-2.03(2H, m), 2.68-2.74(3H, m), 2.95(1H, t), 5.3 (1H, q), 7.44-7.63(7H, m), 7.97-8.0(3H, m), 8.23 (1H, d), 9.32(1H, s), 9.97(lH,s) Mass (m/z)-M+l-358

Claims We Claim:
comprising reduction of compound XVII

1. A process for preparing 3-[3-(trifluoromethyl)phenyl] propanol (compound II)

with reducing agent, in presence of catalyst and a organic base, wherein R is methyl, ethyl, butyl.
2. A process according to claim 1, wherein the reducing agent comprises from alkali metal hydrides such as lithium aluminium hydride, sodium hydride or alkali metal borohydrides such as lithium borohydride, sodium borohydride, preferably sodium borohydride.
3. A process according to claim 1, wherein the catalyst selected from transition metal catalysts like cobaltous chloride hexahydrate.
4. A process according to claim 1, wherein the organic base used comprises from triethylamine, tributylamine, diisopropylethylamine, diisopropylamine, diethylamine, preferably diisopropylamine.

5. A process according to claim 1, wherein the organic solvent selected from mixture of ether and alcohol.
6. A process according to claim 5, wherein the ethers selected from MTBE, DIPE, diethyl ether, tetrahydrofuran, preferably tetrahydrofuran and alcohols selected from methanol, ethanol, isopropanol, preferably methanol.

6. A process according to claim 1, wherein the reaction temperature is of 35-50 °C, preferably 35-40 °C.
7. A process according to claim 1, wherein the Cinacalcet and/or its pharmaceutically acceptable salts and/or solvates preparation comprises
a. oxidation of 3-[3-(trifluoromethyI)phenyl] propanol (compound II)

in a solvent in presence of a base to give 3-[(3-Trifiuoromethyl)phenyl]propanal (compound III);

b. reacting 3-[(3-TrifluoromethyI)phenyl]propanal (compound III) with titanium tetraisopropoxide in a solvent and reverse addition to(lR)-l-(l-naphthyl)ethylamine in presence of reducing agent to provide Cinacalcet base;


c. reacting Cinacalcet base with methyltert-butyl ether hydrochloride in presence of a solvent to give cinacalcet hydrochloride salt
8. A process according to claim according to claim 7a, wherein the oxidizing reagent comprises phosphorus pentoxide in solvent like dichloromethane in presence of dimethylsulfoxide and a base such as organic bases like triethylamine, diisopropylethylamine, diisopropyl amine, trimethylamine, DBU, DBN, preferably triethylamine.
9. A process according to claim 7b, wherein use of 3-[(3-trifluoromethyl)phenyl]propanal (compound III) in the preparation of Cinacalcet base comprises formation of aldehyde-titaniumtetraisopropoxide complex at a temperature 0-30° C, preferably 10-15°C
10. A process according to claim 7b, wherein the solvent used in the formation of
aldehyde-titaniumtetraisopropoxide complex is selected from ethereal solvents like
diethylether, methyltertbutyl ether, diisopropyl ether, tetrahydrofuran, alcohols like
ethanol, methanol, isopropyl alcohol, preferably anhydrous tetrahydrofuran, and reducing
agent used like sodium borohydride.
11. A process according to claim 7c, wherein the solvent used is cyclohexane.

12. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.