US008921606B2

(12) United States Patent (10) Patent N0.: US 8,921,606 B2 Parthasaradhi Reddy et a1. (45) Date of Patent: Dec. 30, 2014

(54) PROCESS FOR CINACALCET (56) References Cited HYDROCHLORIDE U.S. PATENT DOCUMENTS

(75) Inventors: Bandi Parthasaradhi Reddy, 6,211,244 B1 * 4/2001 Van Wagenen et a1...... 514/649 Hyderabad (IN); Kura Rathnakar 7,250,533 B2 * 7/2007 LifshitZ-Liron et al...... 564/336 Reddy, Hyderabad (IN); Dasari 2010/0174119 A1* 7/2010 Ducry et a1...... 568/420 Muralidhara Reddy, Hyderabad (IN); Rapolu Raji Reddy, Hyderabad (IN); FOREIGN PATENT DOCUMENTS J ambula Mukunda Reddy, Hyderabad EP 1990333 A1 11/2008 (IN); Bandi Vamsi Krishna, Hyderabad WO WO-2007/127445 A2 11/2007 (1N) WO WO-2008/035212 A2 3/2008 WO WO-2008/035381 A2 3/2008 Assignee: Hetero Research Foundation, WO WO2008035212 A2 * 3/2008 (73) WO WO-2008/058235 A2 5/2008 Balanagar, Hyderabad (IN) WO WO-2008/068625 A2 6/2008 WO WO-2008/117299 A1 10/2008 Notice: Subject to any disclaimer, the term of this WO WO-2009/153814 A1 12/2009 patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 0 days. Wang et al. Synthesis of Cinacalcet congers. Tetrahedron Letters 45 (2004), 8355-8358.* (21) App1.No.: 13/810,319 Bijukumar et al., Ef?cient Synthesis of Cinacalcet Hydrochloride, Synthetic Communications, 38(10): 1512-1517 (2008). (22) PCT Filed: Jul. 16, 2010 Lednicer, Synthesis and Antifertility Activity of 4- and 5-(0mega arylalkyl) orazolidinethiones, Journal of Medicinal Chemistry, 11: (86) PCT No.: PCT/IN2010/000477 1258-1262 (1968). Sorbera et al., Cinacalcet Hydrochloride, Drugs of the Future, 27(9): § 371 (0X1)’ 831-836 (2002). (2), (4) Date: Jan. 15, 2013 Thiel et al., Practical Synthesis of the Calcimimetic Agent, Cinacalcet, Tetrahedron Letters, 49(1): 13-15 (2008). PCT Pub. No.: WO2012/007954 Wang et al., Synthesis of Cinacalcet congers, Tetrahedron Letters, 45: (87) 8355-8358 (2004). PCT Pub. Date: Jan. 19, 2012 International Search Report PCT/IN10/00477, 1 page (mailed Apr. 25, 201 1). (65) Prior Publication Data Written Opinion PCT/IN10/00477, 5 pages (mailed Apr. 25, 2011). US 2013/0178654 A1 Jul. 11, 2013 * cited by examiner Primary Examiner * Sikarl Witherspoon (51) Int. Cl. (74) Attorney, Agent, or Firm * Choate Hall & Stewart C07C 45/41 (2006.01) LLP; Charles E. Lyon; Thomas H. McLean C07C 209/70 (2006.01) C07C 209/84 (2006.01) (57) ABSTRACT C07C 209/28 (2006.01) 3-[3-(Tri?uoromethyl)phenyl]propionaldehyde is a key (52) US. Cl. intermediate for the preparation of cinacalcet hydrochloride. CPC ...... C07C 45/41 (2013.01); C07C209/70 The present invention provides a novel process for the prepa (2013.01); C07C209/28 (2013.01); C07C ration of 3 -[3-(tri?uoromethyl)phenyl]propionaldehyde. The 209/84 (2013.01) present invention also provides an improved process for USPC ...... 568/435; 564/387 preparation of cinacalcet hydrochloride in high yields. The Field of Classi?cation Search present invention further provides a process for puri?cation (58) of cinacalcet hydrochloride. USPC ...... 568/435; 564/387 See application ?le for complete search history. 20 Claims, No Drawings US 8,921,606 B2 1 2 PROCESS FOR CINACALCET HYDROCHLORIDE Scheme I

FIELD OF THE INVENTION 01 CH3 + 3-[3-(Tri?uoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride. O The present invention provides a novel process for the prepa ration of 3-[3-(tri?uoromethyl)phenyl]propionaldehyde. The l—acetyl naphthalene present invention also provides an improved process for Ti (0— i-Pr)4 preparation of cinacalcet hydrochloride in high yields. The 4P present invention further provides a process for puri?cation HZN of cinacalcet hydrochloride. CF3 3 — [3 —(tri?uorornethyl)phenyl] — propylamine BACKGROUND OF THE INVENTION Sodium Cinacalcet hydrochloride is chemically, (R)-0t-methyl-N N cyanoborohydride [3 - [3 -tri ?uoromethyl)phenyl]propyl] -1 -napthalenemetha / CF3 Methanol namine hydrochloride. Cinacalcet hydrochloride is repre CH3 sented by the following structure: cinacalcet iso—imine

Chiral gWQ LC CF3 —> CH3

30 racemic cinacalcet base (R)—cinacalcet base

Calcimimetics are a class of orally active, small molecules 35 According to the ’244 patent, cinacalcet can be prepared by that decrease the secretion of parathyroid hormone (“PTH”) reacting 3 -?uoromethylcinnamonitrile with diisobutyl alu by activating calcium receptors. The secretion of PTH is minum hydride to give aluminum-imine intermediate, which normally regulated by the calcium- sensing receptor. Calcimi was then reacted with (R)-1-(1-naphthyl)ethylamine, and metic agents increase the sensitivity of this receptor to cal reducing the cinacalcet imine intermediate thus obtained with cium, which inhibits the release of parathyroid hormone, and 40 sodium cyanoborohydride in ethanol. lowers parathyroid hormone levels within a few hours. Cal Process for the preparation of cinacalcet was reported in cimimetics are used to treat hyperparathyroidism, a condition Drug oflhefulure, 2002, 27(9), 831-836. According to the characterized by the over-secretion of PTH that results when journal, cinacalcet can be prepared by reacting (R)-(1-naph calcium receptors on parathyroid glands fail to respond prop thyl)ethylamine with 3-[3-(tri?uoromethyl)phenyl]propi 45 erly to calcium in the bloodstream. Elevated levels of PTH, an onaldehyde in the presence of titanium tetraisopropoxide to indicator of secondary hyperparathyroidism, are associated give cinacalcet imine, which was then reduced with sodium with altered metabolism of calcium and phosphorus, bone cyanoborohydride in ethanol. The synthetic procedure was pain, fractures, and an increased risk for cardiovascular death. illustrated in scheme II, below: Cinacalcet hydrochloride is approved for treatment of sec 50 ondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with cinacalcet hydrochloride Scheme II lowers serum levels of PTH as well as the calcium/phospho rus ion product, a measure of the amount of calcium and phosphorus in the blood. Cinacalcet hydrochloride is mar 55 + keted as Sensipar® in USA and as Mimpara® in Europe. CF3 CH0

Cinacalcet and its pharmaceutical acceptable salts were 3- [3—tri?uorornethyl)phenyl] — disclosed in US. Pat. No. 6,211,244 (herein after referred to propionaldehyde as the ’244 patent). In accordance with the ’244 patent, cina calcet can prepared by reacting 1-acethylnaphthalene with HZN Ti(O— i-Pr)4 3-[3-(tri?oromethyl)phenyl]propylamine in the presence of —> titanium isopropoxide to produce an cinacalcet isoimine, fol lowed by treatment with sodium cyanoborohydride in metha CH3 nol and resolution of the racemic cinacalcet base by chiral 65 liquid chromatography. The synthetic procedure is illustrated in scheme I, below: US 8,921,606 B2 4 -continued The major problem with the direct preparation of the 3-[3 (tri?uoromethyl)phenyl]propionaldehyde from an ester of 3-[3-(tri?uoromethyl)phenyl]propionic acid is that the ques 0 c anoborohSodium dride CF / N y y tion of reproducibility of the aldehyde formation when used 3 Ethanol the reagents such as oxalyl chloride. Another problem with CH3 this conversation is that the over reduction of the aldehyde cinacalcet imine formed to the corresponding undesired alcohol. The present (R)—cinacalcet base invention makes now available a more ef?cient process for the manufacture of cinacalcet hydrochloride in particular by providing ef?cient manufacture of 3-[3-(tri?uoromethyl) Process for the preparation of 3-[3-(tri?uoromethyl)phe phenyl]propionaldehyde. According to the present invention, nyl]propionaldehyde was reported in Tetrahedron letters, 3-[3-(tri?uoromethyl)phenyl]propionaldehyde can prepared (45), 8355-8358, (2004)footnote 12. According to thejour from ester of 3-[3-(tri?uoromethyl)phenyl]propionic acid in nal, 3-[3-(tri?uoromethyl)phenyl]propionaldehyde can be a single step. It has been found that the ester of 3-[3-(tri?uo prepared by reduction of 3-(tri?uoromethyl)cinnamic acid to romethyl)phenyl]propionic acid can be reduced selectively to the corresponding alcohol followed by swern oxidation to the corresponding aldehyde by choosing suitable reaction give the desired aldehyde. The synthetic procedure was illus condition, avoiding the formation of excess of the undesired trated in scheme III, below: corresponding alcohol. 20 2-[3-(Tri?uoromethyl)phenyl]-5-[3-(tri?uoromethyl)phe Scheme HI nyl] -3 -hydroxy pentanal and (R)-1-(naphthyl)ethylamine are potential impurities in cinacalcet hydrochloride. Pd/C/HZ The chemical formula of (R)-1-(naphthyl)ethylamine may —> be represented as: / LAH 25 CF3 COOH Swem oxidation 3 — (tri?uoromethyl)cinnarnic acid

30 01:3 CH0

3 — [3 —tri?uoromethyl)phenyl] — propionaldehyde

35 PCT publication WO 2008/ 035212 disclosed a process for preparing 3 - [3 - (tri?uoromethyl)phenyl] propionaldehyde. According to the publication, 3-[3-(tri?uoromethyl)phenyl] The chemical formula of 2-[3-(tri?uoromethyl)phenyl]-5 propionaldehyde can be prepared by reacting 3-[3-(tri?uo [3-(tri?uoromethyl)phenyl] -3 -hydroxy pentanal may be rep romethyl)phenyl]propan-1-ol with 2,2,6,6-tetramethylpip 40 resented as: eridine-l -oxyl (TEMPO) and sodium hypochlorite in the presence of potassium bromide in methylene chloride. PCT publication WO 2008/ 068625 disclosed a process for the preparation of cinacalcet by reductive amination of 3-(3 tri?uoromethylphenyl)propanal with (R)-1-naphthylethy 45 lamine in the presence of a sodium triacetoxyborohydride. PCT publication WO 2007/ 127445 disclosed a process for the preparation of cinacalcet by reacting 3-(3 -tri?uorometh CF3 CF3 ylphenyl)propanoic acid with R)-1-naphthylethylamine to give N-[(1R)-1-(1-napthyl)ethyl]-3-(3-tri?uoromethyl)phe 50 OH nyl]propanamide, which was then reduced to give cinacalcet and its pharmaceutically acceptable salts. Similar process The present invention is intended to enhance the purity of was also described in PCT publications WO 2008/035381, cinacalcet hydrochloride. In particular, the present invention WO 2008/058235, WO 2008/117299; Tetrahedron Letters is directed to reduce or remove 2-[3-(tri?uoromethyl)phe 2008 49(1), 13-15 and Synthetic communications 2008 55 38(10),1512-1517. nyl]-5-[3-(tri?uoromethyl)phenyl]-3-hydroxy pentanal and PCT publication WO 2009/ 153814 disclosed a process for (R)-1-(naphthyl)ethylamine impurities from cinacalcet the preparation of cinacalcet. According to the publication, hydrochloride. cinacalcet can be prepared by reacting (R)-1-naphthylethy Thus, one object of the present invention is to provide a lamine with 3-(3 -tri?uoromethylphenyl)propenaldehyde to 60 novel process for the preparation of 3-[3-(tri?uoromethyl) give the non isolated (R)-N-[3-[3-(tri?uoromrthyl)phenyl] phenyl]propionaldehyde. 2-propenylimino-N-[1-(1-napththyl)ethylamine, which was then reduced with sodium borohydride in methanol and Another object of the present invention is to provide an hydrogenating the cinacalcet imine intermediate thus improved process for the preparation of cinacalcet hydro chloride. obtained. 65 3-[3-(Tri?uoromethyl)phenyl]propionaldehyde is a key Yet another object of the present invention is to provide a intermediate for the preparation of cinacalcet hydrochloride. process for the puri?cation of cinacalcet hydrochloride. US 8,92l,606 B2 5 6 SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provided a novel pro The term “room temperature” refers to temperature at cess for the preparation of 3-[3-(tri?uoromethyl)phenyl]pro about 25 to 35° C. pionaldehyde of formula I, According to one aspect of the present invention, there is provided a novel process for the preparation of 3-[3-(tri?uo romethyl)phenyl]propionaldehyde of formula I,

0113 CHO

0113 CHO which comprises, reducing the methyl 3-[3-(tri?uoromethyl) phenyl]propanoate of formula II which comprises, reducing the methyl 3-[3-(tri?uoromethyl) phenyl]propanoate of formula II

20

0113 COOR'

0113 COOR' wherein R' is lower alkyl. 25 with diisobutylaluminium hydride (DIBAL-H) in an hydro wherein R' is lower alkyl. carbon solvent, an chlorinated solvent, an ether solvent or with diisobutylaluminium hydride (DIBAL-H) in an hydro mixtures thereof below —400 C. to obtain a compound of carbon solvent, an chlorinated solvent, an ether solvent or formula I. 30 mixtures thereof below —400 C. to obtain a compound of In another aspect, the present invention provided a novel formula I. process for the preparation of 3-[3-(tri?uoromethyl)phenyl] The term “lower alkyl” refers to Cl-C4 alkyl. Preferably propionaldehyde, which comprises: alkyl may be selected from methyl or ethyl, and more prefer a) reducing the methyl 3-[3-(tri?uoromethyl)phenyl]pro able alkyl is methyl. panoate with diisobutylaluminium hydride (DIBAL-H) 35 The solvent used in the process may preferably be selected in an hydrocarbon solvent, an chlorinated solvent, an from the group consisting of cyclohexane, cyclohexene, ether solvent or mixtures thereof below —400 C.; cycloheptane, cyclopentane, n-hexane, n-heptane, benzene, b) quenching the reaction mass with an alcohol solvent; toluene, xylene, dichloromethane, chloromethane, dichloro ethane, chloroform, carbon tetrachloride, chlorobenzene, tet c) adding ethyl acetate to the reaction mass obtained in step rahydrofuran, diisopropyl ether, tertrahydropyran, l,4-diox (b); ane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl d) separating out the solids; and ether, di-tert-butyl ether, diglyme, dimethoxyethane, e) isolating 3 - [3 -(tri?uoromethyl)phenyl]propionaldehyde dimethoxymethane and methoxyethane. More preferable sol from the mother liquor. vents are n-hexane, cyclohexane, toluene, dichloromethane, 5 diisopropyl ether and tetrahydrofuran, and still more prefer In another aspect, the present invention provided an able solvents are n-hexane, toluene, dichloromethane and improved process for the preparation of cinacalcet hydro tetrahydrofuran. chloride in high yields, which comprises: The reaction mass may preferably be maintained in the a) adding 3-[3-(tri?uoromethyl)phenyl]propionaldehyde process below —50° C. and more preferable at about —70 to to (R)-(l-naphthyl)ethylamine in ether solvent in the 50 —85° C. presence of titanium(IV)isopropoxide below —5° C.; According to another aspect of the present invention, there b) reacting sodium cyanoborohydride with the reaction is provided a novel process for the preparation of 3-[3-(trif mass obtained in step (a); luoromethyl)phenyl]propionaldehyde, which comprises: a) reducing the methyl 3-[3-(tri?uoromethyl)phenyl]pro c) concentrating the reaction mass; panoate with diisobutylaluminium hydride (DIBAL-H) d) adding ether solvent, hydrochloride in an organic sol in an hydrocarbon solvent, an chlorinated solvent, an vent and water to the residual mass obtained in step (c); ether solvent or mixtures thereof below —400 C.; and b) quenching the reaction mass with an alcohol solvent; e) isolating cinacalcet hydrochloride. c) adding ethyl acetate to the reaction mass obtained in step Yet another aspect, the present invention provided a pro 60 (b); cess for the puri?cation of cinacalcet hydrochloride, which d) separating out the solids; and comprises: e) isolating 3-[3-(tri?uoromethyl)phenyl]propionaldehyde from the mother liquor. a) stirring cinacalcet hydrochloride with a solvent system The solvent used in step (a) may preferably be selected comprising water and solvent selected from alcohol sol from the group consisting of cyclohexane, cyclohexene, vent, nitrile solvent and mixture thereof; and cycloheptane, cyclopentane, n-hexane, n-heptane, benzene, b) isolating substantially pure cinacalcet hydrochloride. toluene, xylene, dichloromethane, chloromethane, dichloro US 8,921,606 B2 7 8 ethane, chloroform, carbon tetrachloride, chlorobenzene, tet Cinacalcet hydrochloride may be isolated in step (e) by rahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-diox methods known such as ?ltration or centrifugation. ane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl According to another aspect of the present invention, there ether, di-tert-butyl ether, diglyme, dimethoxyethane, is provides a process for the puri?cation of cinacalcet hydro dimethoxymethane and methoxyethane. More preferable sol chloride, which comprises: vents are n-hexane, cyclohexane, toluene, dichloromethane, a) stirring cinacalcet hydrochloride with a solvent system diisopropyl ether and tetrahydrofuran, and still more prefer comprising water and solvent selected from alcohol sol able solvents are n-hexane, toluene, dichloromethane and vent, nitrile solvent and mixture thereof; and tetrahydrofuran. b) isolating substantially pure cinacalcet hydrochloride. The reaction mass may preferably be maintained in step (a) The term “substantially pure cinacalcet hydrochloride” below —50° C. and more preferable at about —70 to —85° C. refers to cinacalcet hydrochloride having the purity greater The alcohol solvent used in step (b) may preferably be a than about 98% by weight, preferably greater than about 99% solvent or mixture of solvents selected from methanol, etha by weight, and more preferably greater than about 99.5% by nol, isopropyl alcohol, isobutanol and n-butanol, and more weight. preferable alcohol solvent is methanol. The alcohol solvent used in step (a) may preferably be The separated solids may be collected by the method selected from methanol, ethanol, isopropyl alcohol, isobu known such as centrifugation or ?ltration. tanol or n-butanol, and more preferable alcohol solvent is Isolation of 3-[3-(tri?uoromethyl)phenyl]propionalde methanol. hyde in step (e) can be performed by conventional methods The nitrile solvent used in step (a) may preferably be such as cooling, removal of solvents, concentrating to the 20 selected from acetonitrile, propionitrile, butyronitrile or ben reaction mass, adding an anti-solvent, extraction with a sol zonitrile, and more preferable nitrile solvent is acetonitrile. vent and the like. The step (a) is preferably carried out at elevated tempera According to another aspect of the present invention, there ture. The term “elevated temperature” refers to temperature at is provided an improved process for the preparation of cina above 25° C. More preferably the step (a) is carried out at calcet hydrochloride in high yields, which comprises: 25 about 40 to 100° C. and still more preferably at about 45 to 90° a) adding 3-[3-(tri?uoromethyl)phenyl]propionaldehyde C. to (R)-(1-naphthyl)ethylamine in ether solvent in the Isolation of highly pure cinacalcet hydrochloride may pref presence of titanium(lV)isopropoxide below —5° C.; erably be carried out by methods known such as ?ltration or b) reacting sodium cyanoborohydride with the reaction centrifugation. mass obtained in step (a); 30 The puri?cation process yields cinacalcet hydrochloride c) concentrating the reaction mass; with reduced levels of impurities, speci?cally, 2-[3-(tri?uo d) adding ether solvent, hydrochloride in an organic sol romethyl)phenyl] - 5 - [3 -(tri?uoromethyl)phenyl] -3 -hydroxy vent and water to the residual mass obtained in step (c); pentanal and (R)- 1 -(naphthyl)ethylamine. and The purity of cinacalcet hydrochloride is measured by e) isolating cinacalcet hydrochloride. 35 High performance liquid chromatography (HPLC). The ether solvent used in step (a) may preferably be a The invention will now be further described by the follow solvent or mixture of solvents selected from tetrahydrofuran, ing examples, which are illustrative rather than limiting. diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl EXAMPLES ether, diglyme, dimethoxyethane, dimethoxymethane and 40 methoxyethane, and more preferable ether solvents are tet Example 1 rahydrofuran and diisopropyl ether. The reaction in step (a) may preferably be carried out at Preparation of below —20° C. and more preferable at about —30 to —60° C. 3 - [3 -(tri?uoromethyl)phenyl]propionic acid Preferably the reaction mass is concentrated in step (c) by 45 distilling off the solvent. The distilling off the solvent may be Palladium carbon (10%, 6 gm) was added to water (20 ml) carried out at atmospheric pressure or at reduced pressure. and then added 3-(tri?uoromethyl)cinnamic acid (100 gm) The distillation may preferably be carried out until the solvent and toluene (1000 ml). The resulting contents were hydroge is almost completely distilled off. nated with hydrogen gas at a pressure of 4 kg at 45 to 50° C. The ether solvent used in step (d) may preferably be a 50 for 2 hour 30 minutes. The reaction mass was then ?ltered solvent or mixture of solvents selected from tetrahydrofuran, through celite bed and the layers were separated. The organic diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert layer was dried over sodium sulfate and the solvent was butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl distilled off under reduced pressure to obtain 98.7 gm of ether, diglyme, dimethoxyethane, dimethoxymethane and 3-[3-(tri?uoromethyl)phenyl]propionic acid. methoxyethane, and more preferable ether solvents are tet 55 rahydrofuran and diisopropyl ether. Example-2 The organic solvent used in step (d) may preferably be a solvent or mixture of solvents selected from the group con Preparation of methyl sisting of an ether solvents such as tetrahydrofuran, diisopro 3-[3-(tri?uoromethyl)phenyl]propanoate pyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl 60 ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, 3-[3-(Tri?uoromethyl)phenyl]propionic acid (100 gm) as diglyme, dimethoxyethane, dimethoxymethane and meth obtained in example 1 was dissolved in methanol (250 ml) oxyethane; an ester solvents such as ethyl acetate, methyl and then added concentrated sulfuric acid (45 gm) slowly for acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl 25 minutes. The temperature of the reaction mass was raised formate. More preferable organic solvents are diisopropyl 65 to 40 to 45° C. and maintained for 1 hour at 30 to 45° C. The ether and ethyl acetate, still more preferable organic solvent is methanol solvent was distilled off under vacuum at below 45 ° ethyl acetate. C. to obtain residual mass. To the residual mass was added US 8,921,606 B2 10 water (600 ml) and methylene dichloride (500 ml). The sepa —45 to —500 C. To the solution was added a solution of rated organic layer was dried over sodium sulfate and the (R)-(1-naphthyl)ethylamine (5 gm) in tetrahydrofuran (75 solvent was distilled off under reduced pressure to obtain 99.2 ml) at —45 to —500 C. slowly for 2 hours 30 minutes and then gm of methyl 3-[3-(tri?uoromethyl)phenyl]propanoate. added titanium(lV)isopropoxide (2.07 gm). The reaction mass was stirred for 20 minutes at —45 to —500 C. and then Example-3 added a solution of sodium cyanoborohydride (2 gm) in Preparation of methanol (20 ml) slowly for 20 minutes. The temperature of 3-[3-(tri?uoromethyl)phenyl]propionaldehyde the reaction mass was raised to room temperature and main tained for 2 hours at room temperature. To the reaction mass Methyl 3-[3-(tri?uoromethyl)phenyl]propanoate (5 gm) as was added water (25 ml) and the reaction mass was then obtained in example 2 was added to toluene (50 ml) and then ?ltered through celite bed. The layers were separated and the cooled to —75 to —800 C. To the solution was added a solution aqueous layer was extracted with diisopropyl ether. The com of diisobutylaluminium hydride (4.59 gm) in n-hexane (33 bined organic layer was dried over sodium sulfate and the ml) slowly for 1 hour 30 minutes at —75 to —800 C. The solvent was distilled off under reduced pressure to obtain reaction mass was maintained for 1 hour at —75 to —800 C. and residual mass. To the residual mass was added diisopropyl then added methanol (5 ml) at —75 to —800 C. The temperature ether (40 ml) and water (50 ml). The contents were heated to of the reaction mass was raised to 0° C. and the reaction mass 55 to 600 C. Hydrochloride in ethyl acetate (16% HCl, 6.2 ml) was poured to the chilled water (1 50 ml). To the reaction mass was added to the reaction mass at 55 to 600 C. and maintained was added ethyl acetate (50 ml) and then added sodium sul for 30 minutes at 55 to 600 C. The reaction mass was cooled fate solution (20%, 25 ml). The reaction mass was maintained 20 to room temperature and maintained for 15 hours at room for 1 hour 30 minutes at room temperature and then ?ltered temperature, ?ltered. The solid obtained was dried to obtain through celite bed. The layers were separated and the aqueous 9.5 gm of cinacalcet hydrochloride. layer was extracted with toluene. The combined organic layer Cinacalcet hydrochloride: 98.6%; was dried over sodium sulfate and the solvent was distilled off 2 - [3 - (Tri?uoromethyl)phenyl] -5 - [3 -(tri?uoromethyl)phe under reduced pressure to obtain 4.2 gm of 3-[3-(tri?uorom ethyl)phenyl]propionaldehyde. 25 nyl]-3-hydroxy pentanal impurity: 1.05%; 3-[3-(Tri?uoromethyl)phenyl]propionaldehyde: 99.2%; (R)-1 -(Naphthyl)ethylamine impurity: 0.3%. 3-[3-(Tri?uoromethyl)phenyl]propanol impurity: 0.3%. Example 6 Example 4 30 Preparation of Cinacalcet Hydrochloride Preparation of Cinacalcet Hydrochloride 3-[3-(Tri?uoromethyl)phenyl]propionaldehyde (142 gm) 3-[3-(Tri?uoromethyl)phenyl]propionaldehyde (14.2 gm) was dissolved in diisopropyl ether (500 ml) and then cooled to as obtained in example 3 was dissolved in tetrahydrofuran (50 —45 to —500 C. To the solution was added a solution of ml) and then cooled to —45 to —500 C. To the solution was 35 (R)-(1-naphthyl)ethylamine (100 gm) in diisopropyl ether added a solution of (R)-(1-naphthyl)ethylamine (10 gm) in (1400 ml) at —45 to —500 C. slowly for 2 hours 30 minutes and tetrahydrofuran (150 ml) at —45 to —500 C. slowly for 2 hours then added titanium(lV)isopropoxide (41 gm). The reaction 30 minutes and then added titanium(lV)isopropoxide (4.1 mass was stirred for 15 minutes at —45 to —500 C. and then gm). The reaction mass was stirred for 15 minutes at —45 to added a solution of sodium cyanoborohydride (40 gm) in —500 C. and then added a solution of sodium cyanoborohy 40 methanol (380 ml) slowly for 20 minutes. The temperature of dride (4 gm) in methanol (40 ml) slowly for 20 minutes. The the reaction mass was raised to room temperature and main temperature of the reaction mass was raised to room tempera tained for 2 hours at room temperature. To the reaction mass ture and maintained for 2 hours at room temperature. To the was added water (450 ml) and the reaction mass was then reaction mass was added water (50 ml) and the reaction mass ?ltered through celite bed. The layers were separated and the was then ?ltered through celite bed. The layers were sepa 45 aqueous layer was extracted with diisopropyl ether. The com rated and the aqueous layer was extracted with diisopropyl bined organic layer was dried and the solvent was distilled off ether. The combined organic layer was dried and the solvent under reduced pressure to obtain residual mass. To the was distilled off under reduced pressure to obtain residual residual mass was added diisopropyl ether (700 ml) and water mass. To the residual mass was added diisopropyl ether (80 (1000 ml). The contents were heated to 55 to 600 C. Hydro ml) and water (100 ml), and then heated to 55 to 60° C. 50 chloride in diisopropyl ether (16% HCl, 125 ml) was added to Hydrochloride in diisopropyl ether (16% HCl, 12.5 ml) was the reaction mass at 55 to 600 C. and maintained for 30 added to the reaction mass at 55 to 600 C. and maintained for minutes at 55 to 600 C. The reaction mass was cooled to room 30 minutes at 55 to 600 C. The reaction mass was cooled to temperature and maintained for 15 hours at room tempera room temperature and maintained for 15 hours at room tem ture, ?ltered. The solid was dried to obtain 175 gm of cina perature. The separated solid was ?ltered and dried to obtain 55 calcet hydrochloride. 18 gm of cinacalcet hydrochloride. Cinacalcet hydrochloride: 98.5%; Cinacalcet hydrochloride: 98.5%; 2 - [3 - (Tri?uoromethyl)phenyl] -5 - [3 -(tri?uoromethyl)phe 2 - [3 - (Tri?uoromethyl)phenyl] - 5 - [3 -(tri?uoromethyl)phe nyl]-3-hydroxy pentanal impurity: 1.08%; nyl]-3-hydroxy pentanal impurity: 1.08%; (R)-1 -(Naphthyl)ethylamine impurity: 0.32%. (R)-1 -(Naphthyl)ethylamine impurity: 0.32%. 60 Example 7 Example 5 Puri?cation of Cinacalcet Hydrochloride Preparation of Cinacalcet Hydrochloride 65 Cinacalcet hydrochloride (10 gm) as obtained in example 4 3-[3-(Tri?uoromethyl)phenyl]propionaldehyde (7.07 gm) was dissolved in a mixture of water (125 ml) and methanol was dissolved in tetrahydrofuran (25 ml) and then cooled to (15 ml). The reaction mass was stirred for 1 hour at room US 8,921,606 B2 11 12 temperature and ?ltered. The solid obtained was dried at 60 to 3. The process according to claim 1, wherein the solvent 65° C. for 6 hours to obtain 9.2 gm of substantially pure used in the process is selected from the group consisting of cinacalcet hydrochloride. cyclohexane, cyclohexene, cycloheptane, cyclopentane, Cinacalcet hydrochloride: 99.96%; n-hexane, n-heptane, benzene, toluene, xylene, dichlo 2-[3-(Tri?uoromethyl)phenyl]-5-[3-(tri?uoromethyl)phe- 5 romethane, chloromethane, dichloroethane, chloroform, car nyl]-3-hydroxy pentanal impurity: Not detected; bon tetrachloride, chlorobenzene, tetrahydrofuran, diisopro (R)-1-(Naphthyl)ethylamine impurity: Not detected. pyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, Example 8 diglyme, dimethoxyethane, dimethoxymethane, methoxy 10 ethane, and mixtures thereof. Puri?cation 0f Cinacalcet Hydrochloride 4. The process according to claim 3, wherein the solvent is selected from the group consisting of n-hexane, cyclohexane, Cinacalcet hydrochloride (10 gm) W85 suspended in a nliX- toluene, dichloromethane, diisopropyl ether, tetrahydrofuran, ture of water (80 ml) and acetonitrile (20 ml). The contents and mixtures thereof, were heated to 80° C. and stirred for 20 minutes at 80° C. to i 5 5~ The process according to claim 4, Wherein the the sol obtain solution. The solution was cooled to at room tempera- vent is selected from the group consisting of n-hexane, tolu ture and maintained fOr 2 hours. The separated SOlid W85 ene, dichloromethane, tetrahydrofuran, andmixtures thereof. ?ltered and dried to obtain 8.3 gm of substantially pure cina- 6_ The process according to claim 1, wherein the reaction calcet hydrochloride. mass is maintained in the process below —50° C. Cinacalcet hydrochloride: 99.6%; 20 7. The process according to claim 6, wherein the reaction 2-[3-(Tri?uoromethyl)phenyl]-5-[3-(tri?uoromethyl)phe- mass is maintained at about -70 to -85° C, ny1]-3-hydroxy pentanal impurity: NOI deIeeIed; 8. A process for the preparation of 3-[3-(tri?uoromethyl) (R)-1-(Naphthy1)ethy1amine impurity: 0.11%. phenyl]propionaldehyde, which comprises: (a) reducing methyl 3-[3-(tri?uoromethyl)phenyl]pro Example 9 25 panoate with diisobutylaluminium hydride (DIBAL-H) in an hydrocarbon solvent, an chlorinated solvent, an Puri?cation Of Cinacalcet HydrOChloride ether solvent or mixtures thereof below —40° C.; (b) quenching the reaction mass with an alcohol solvent; Cinacalcet hydrOChloride (10 gm) was dissowed in metha' (c) adding ethyl acetate to the reaction mass obtained in nol (15 ml). To the solution was added water (125 ml) slowly 30 step (b); for 40 minutes to form precipitation. The reaction mass was (d) separating out the solids; and stirred for 2 hour at room temperature and ?ltered. The solid (e) isolating 3_[3-(tri?uoromethyl)pheny11propiona1de_ obtained was dried to obtain 9.3 gm of substantially pure hyde from the mother liquon Cinacalcet hydrOChloridQ 9. The process according to claim 8, wherein the solvent Cinacalcet hydrOChloridei 99-98%; 35 used in step (a) is selected from the group consisting of 2'[3'(T??uoromethyl)phenyll'5'13'(tr i?uor OHlethYDPhe' cyclohexane, cyclohexene, cycloheptane, cyclopentane, nyll'3'hydroxy pentanal impurity? N01 demoted; n-hexane, n-heptane, benzene, toluene, xylene, dichlo (R)'1'(NaPhthy1)ethy1amine impurity? N01 deteCted- romethane, chloromethane, dichloroethane, chloroform, car _ bon tetrachloride, chlorobenzene, tetrahydrofuran, diisopro We 01mm: _ _ 40 pyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl 1' A Procéss for the Preparanon Of 3'[3'(m?u0r0methyl) ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, phenyl]proplonaldehyde Of formula L diglyme, dimethoxyethane, dimethoxymethane, methoxy ethane, and mixtures thereof. 10. The process according to claim 8, wherein the reaction 45 mass is maintained in step (a) below —50° C. 11. The process according to claim 8, wherein the alcohol solvent used in step (b) is selected from the group consisting

CF3 CHO of methanol,_ ethanol, isopropyl alcohol, isobutanol, n-bu tanol, and mixtures thereof. 50 12. The process according to claim 11, wherein the alcohol which comprises, reducing methyl 3-[3-(tri?uoromethyl) solvent is methan01_ phenyl]propanoate Of fOI‘Innla H 13. A process for the preparation of cinacalcet hydrochlo ride, which comprises: (a) adding 3-[3-(tri?uoromethyl)phenyl]propionaldehyde H 55 to (R)-(1-naphthyl)ethylamine in ether solvent in the presence of titanium(lV)isopropoxide below —5° C.; (b) reacting sodium cyanoborohydride with the reaction CF COOR, mass obtained in step (a); 3 (c) concentrating the reaction mass; 60 (d) adding ether solvent, hydrochloride in an organic sol wherein R' is lower alkyl, vent and water to the residual mass obtained in step (c); with diisobutylaluminium hydride (DIBAL-H) in an and hydrocarbon solvent, an chlorinated solvent, an ether (e) isolating cinacalcet hydrochloride. solvent or mixtures thereof below —40° C. to obtain a 14. The process according to claim 13, wherein the ether compound of formula I. 65 solvent used in step (a) and step (d) is independently selected 2. The process according to claim 1, wherein the R' is from the group consisting of tetrahydrofuran, diisopropyl methyl or ethyl. ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, US 8,921,606 B2 13 14 ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, dig lyme, dimethoxyethane, dimethoxymethane, methoxy ethane, and mixtures thereof. 15. The process according to claim 13, Wherein the reaction in step (a) is carried out below —200 C. 16. The process according to claim 13, Wherein the organic solvent used in step (d) is selected from the group consisting of an ether solvent, an ester solvent, and mixtures thereof. 17. A process for the puri?cation of cinacalcet hydrochlo ride, Which comprises: (a) stirring cinacalcet hydrochloride With a solvent system comprising water and solvent selected from alcohol sol vent, nitrile solvent and mixture thereof; and (b) isolating substantially pure cinacalcet hydrochloride. 18. The process according to claim 17, Wherein the alcohol solvent used in step (a) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, isobutanol, n-bu tanol, and mixtures thereof. 19. The process according to claim 17, Wherein the nitrile solvent used in step (a) is selected from the group consisting 20 of acetonitrile, propionitrile, butyronitrile, benzonitrile, and mixtures thereof. 20. The process according to claim 17, Wherein the step (a) is carried out at above 25° C. 25 * * * * *