FIELD OF THE INVENTION
The present invention relates to a novel process for preparing amine derivatives of formula 1, as calcimimetics,(Formula Reomoved)
wherein Ar1 or Ar2 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alky I, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2, CN, acetoxy; q is 0-2; and R is H,
and pharmaceutically acceptable salts and complexes thereof, by reducing novel amide
intermediates of formula II H(Formula Reomoved)
wherein Ar1, Ar2 and q are same as described above.
Particularly the present invention relates to an industrially advantageous process for the preparation of cinacalcet hydrochloride. The present invention also relates to novel synthetic intermediates useful in the process of the present invention.
BACKGROUND OF THE INVENTION
Calcimimetics are small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR) in the parathyroid glands and other tissues. They lower the threshold for CaSR activation by extracellular calcium ions and diminish parathyroid hormone (PTH) release from parathyroid cells. By targeting the molecular mechanism that modulates PTH secretion on a minute-to-minute basis, calcimimetic compounds offer a novel approach to managing excess PTH secretion in several clinical disorders.
Amine derivative of formula I were disclosed in PCT application WO 94/18959, United States patent nos. 6,211,244, 6,313,146, 6,031,003, 6,001,068, 6,011,884, 5,962,314, 5,858,684, 5,841,368, 5,763,569, 5,688,938 etc.
(Formula Reomoved)wherein Ar1 or Ar2 is either naphthyl or phenyl optionally substituted with 0 to 5, q is 0-2; and R is H, lower alkyl.
The method disclosed in the above patents for the preparation of these compounds includes the reductive amination of a commercially available aldehyde or ketone with a primary amine in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride and titanium isopropoxide.
Alternatively some compounds were prepared from the condensation of a primary amine with an aldehyde or ketone in the presence of titanium (IV) isopropoxide. The resulting intermediate imines were then reduced in situ by the action of sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride. Optionally the intermediate enamine was catalytically reduced using palladium dihydroxide on carbon.
Various compounds were prepared by a diisobutylaluminum hydride (DIBAL-H) mediated condensation of an amine with a nitrile. The resulting intermediate imine is reduced in situ by the action of sodium cyanoborohydride or sodium borohydride. The intermediate alkenes were reduced by catalytic hydrogenation in ethanol using palladium on carbon. Further the compounds obtained were converted to their corresponding salts by treatment of the free base with acid in a suitable solvent.
An important drug that acts as a calcimimetic agent is cinacalcet hydrochloride and is chemically known as N-(l-naphthalen-l-ylethyl)-3-[3-(trifluoromethyl)phenyl]-propan-l-amine hydrochloride. Cinacalcet hydrochloride of formula III,
(Formula Reomoved)is used to treat hyperparathyroidism (elevated parathyroid hormone levels), a consequence of parathyroid tumors and chronic renal failure. The above patents are completely silent about the specific process for the preparation of cinacalcet.
The prior art processes use expensive reagents and are not amenable to an industrial scale up. In view of this, it is the principal object of the present invention to provide an efficient and novel process for the preparation of pure amine derivatives of formula I, which is unique with respect to its simplicity, cost effectiveness and convenience to operate on industrial scale.
Another object of the present invention is to provide novel intermediates that play a crucial role in the preparation of amine derivatives as calcimimetics. Another main object of the present invention is to provide an efficient and cost-effective method for the preparation of highly pure cinacalcet hydrochloride in high yield.
SUMMARY OF THE INVENTION
Accordingly, the present invention teaches an efficient and industrially advantageous process for the preparation of amine derivative of formula I(Formula Reomoved)
wherein Art and Ar2 is either naphthyl or phenyl optionally substituted with 0 to 5 substituents each independently selected from the group consisting of lower alkyl, halogen, lower alkoxy, lower thioalkyl, methylene dioxy, lower haloalkyl, lower haloalkoxy, OH, CH2OH, CONH2i, CN, acetoxy: q is 0-2; and R is H,
and pharmaceutically acceptable salts and complexes thereof by reducing novel amide intermediate of formula II, (Formula Reomoved)
wherein Art, Ar2 and q are as described above.
Another object of the present invention is to provide a process for the preparation of amide
intermediate of formula II (Formula Reomoved)
wherein Ar\, Ar2 and q are as described above,
which comprises introducing an acyl group of the formula IV, (Formula Reomoved)
wherein X = H or halo, wherein halo can be chloro, bromo or (he like; Ar/ is as described above,
into the amino group of molecule of formula V or a salt thereof. (Formula Reomoved)
wherein Ar2 is as described above.
The present invention is also directed to a process, wherein introduction of acyl moiety into amino group is performed by reacting a compound of formula V or a salt thereof, (Formula Reomoved)wherein Ar? is as described above
with a compound of formula VI or a salt or reactive derivative thereof. (Formula Reomoved)wherein Ar1 andX are as described above
Another object of the present invention is to provide a process for the .preparation of
compound of formula VI, (Formula Reomoved)wherein Art andX are as described above
from amino compound of formula VII. (Formula Reomoved)Yet another object of the present invention is to provide a novel and efficient process for the preparation of cinacalcet of formula Ilia and pharmaceutically acceptable acid addition salt thereof
(Formula Reomoved)using novel intermediate of formula VIII, (Formula Reomoved)wherein X = H or halo, wherein halo can be chloro, bromo or the like.
One another object of the present invention is to provide novel intermediates, their pharmaceutically acceptable salts, including solvates, hydrates, enantiomers and the preparation thereof along with processes for the preparing the same and its conversion to cinacalcet hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a new and efficient process for preparing amine derivative of formula I, (Formula Reomoved)
wherein Ar1, Ar2i R and q are as described above starting from amino compound of formula VII.
According to one embodiment of the present invention, the amine derivative of formula I is formed by initially introducing an acyl group of the formula IV, (Formula Reomoved)
wherein X is H or halo;, halo can be chloro, bromo or the like while Art is as described above,
into the amino group of molecule of formula V or a salt thereof, (Formula Reomoved)
wherein Ar2 is as described above,
under conditions effective to produce compounds of formula I in high yield and purity.
One method of synthesizing amine derivatives of formula I is by acylating a compound of formula V or a salt thereof, with a compound of formula VI or a salt or a reactive derivative thereof, and reducing the resulting compound of formula II.
The acylation reaction can be conducted advantageously and smoothly in the presence of a solvent. As said solvent, use may be made of the common solvents and their mixtures unless such solvents do not interfere with the present reaction. There may be mentioned, therefore, such solvents as water, acetone, tetrahydrofuran, toluene, ethylbenzene, xylene, isopropylether, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethylene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether and the like. This reaction may proceed more advantageously when to the solvent there is added a suitable base selected from organic tertiary amine such as pyridine, triethylamine, N,N-dimethylaniline or inorganic base like alkali metal bicarbonate, carbonate, hydroxide, alkaline earth metal carbonate, hydroxide and the like. While the reaction temperature is virtually optional, the reaction usually is carried out under cooling or at room temperature. The reaction is generally completed within several minutes to several hours.
The starting materials used in the preparation of amine derivative of formula I are either procured from the market or prepared by the conventional methods. The compound of formula V is commercially available or prepared by the methods known in the prior art. The compound of formula VI is prepared by different methods starting from amino compound of formula VII.
The present invention also teaches a process of preparing compound of formula VI, (Formula Reomoved)are as described above,
by reacting amine of formula VII, (Formula Reomoved)
wherein Art, is as described above,
with alkene derivative of formula CH2=CHR" in the presence of diazotization reagents, acid and catalyst to afford a compound of formula X. (Formula Reomoved)
wherein R" can be selected from CN, CONR'R2, COOR', wherein R' is hydrogen or an alkyl group, R and R2 can be independently selected from H or lower alkyl group, while X is selected from H, halo, provided both R' and X cannot be H simultaneously.
As the diazotization reagents, nitrous acids, alkyl nitrites, nitrogen dioxide, nitrosyl chloride, the like are conveniently employed and, among them, sodium nitrite and amyl nitrite, are generally used. The reaction is generally conducted in the presence of an acid at a selected temperature within the range of -20 to 20°C for a selected time of one to several hours. The acid employed in the reaction is exemplified by hydrochloric acid, hydrobromic acid, or the like and catalyst can be selected from copper (II) oxide, copper (I) oxide, copper halides like copper chloride, copper bromide and the like. The solvent used can be selected from water, acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, alcohols having CrC4 alkyl group and mixtures thereof.
The compound of formula X, wherein R"=CN, CONR1R2 or COOR', R'is alkyl, X=halo may be further transformed into corresponding acid of formula VI, by using conventional methods such as hydrolysis, reduction, and hydrodehalogenation.
According to one embodiment of the present invention, the compound of formula X, wherein R" is CN, and X=halo, is hydrodehalogenated to form intermediate of formula X, wherein R"-CNandX=H. This intermediate is further hydrolysed to corresponding acid using acid catalyzed or base catalyzed hydrolysis to afford a compound of formula VI.
According to another embodiment of the present invention, the compound of formula X, wherein R" is CN, CONR'R2 or COOR', R' is alkyl, andXis halo, is first hydrolysed in the presence of acid or base to afford an intermediate of formula VI, wherein R" is COOH and X

is halo. This intermediate is further hydrodehalogenated to afford compound of formula VI, wherein X=H.
The acid and basic hydrolysis of the above nitrile, amide or ester derivative of compound of formula X may also be carried out by the methods reported in prior art.
Hydrodehalogenation can be conducted by using sodium dithionite, zinc-acetic acid, zinc-potassium iodide, or magnesium, catalytic dehydrogenation, metal catalyst selected from platinum, ruthenium, osmium, iridium, and especially palladium, raney-nickel, along with a suitable solvent chosen from water, alcohol having C1-C4 alkyl group, tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane, the like and mixtures thereof. Preferably the reaction can favorably be conducted in the presence of zinc, acetic acid and water.
The above reactions can be carried out advantageously in the presence of solvent. Any solvent which can dissolve both starting materials may be employed so far as it does not disturb the reaction, and more preferably one is exemplified by alcohols such as methanol, ethanol, propanol, the like, ketones such as acetone, methyl ethyl ketone, the like, ethers such as ether, tetrahydrofuran, dioxane, the like, or mixture thereof.
The introduction of acyl group to amino group is accomplished by converting acid derivative of formula X ( R" is COOH) or formula VI to the corresponding reactive derivative like acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester thereof.
Preferably acylation is carried out by reacting acid chloride derivative of compound of formula VI, with a compound of formula V to prepare compound of formula II, which is further reduced to obtain compound of formula I.
The reduction conditions employed for reducing compound of formula II may be selected from the known reduction methods and preferably catalytic reduction employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, etc., reduction means employing nascent hydrogen obtained by the
co-existence of metals such as sodium, sodium amalgam, aluminum amalgam etc. and water, alcohols, etc. reduction means employing metallic hydride complexes such as lithium aluminum hydride, diethyl aluminum hydride, sodium aluminum hydride, sodium borohydride, with additives such as iodine, sulfuric acid, lewis acids etc., reduction means treating with metals such as zinc, iron, etc. in solvents such as acetic acid, formic acid, or aqueous mixture thereof, and in the presence of borane complexes selected from amongst borane-tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane-triphenylphosphine and the like. The reaction conditions such as reaction temperature, pressure, sort of the solvent, reaction time and others may be selected suitably according to sort of starting material and reduction means etc.
In yet another embodiment, the present invention is directed to amide intermediate of formula IX, (Formula Reomoved)
wherein Art, Ar2i X and q are as described above, prepared by direct acylation of compound of formula VI with compound of formula V.
The amide intermediate of formula IX is then converted to compound of formula II by hydrodehalogenation. While hydrodehalogenation of compound of formula IX can be performed by reaction with zinc in the presence of inorganic or organic acid like acetic acid, hypophosphorous acid and the like along with water with or without using organic solvents such as toluene, xylene, hexane, tetrahydrofuran, isopropylether, methyltertiarybutylether, dioxane and the like and mixture thereof.
In another embodiment of the present inventioiijjhe amide intermediate of formula II can also be prepared by reacting a compound of formula XI, (Formula Reomoved)wherein Ar2 is as defined above,
with amino compound of formula VII(Formula Reomoved)
wherein Ar1 is as defined above.
The above reaction can be conducted in the presence of sodium nitrite, acid and catalytic amount of catalyst. The acid used in the above transformation can be selected from hydrochloric acid, hydrobromic acid or the like and catalyst can be selected from copper (II) oxide, copper (I) oxide, copper halide and the like.
While according to yet another embodiment of the present invention, calcimimetic agents of formula I can be converted to pharmaceutically acceptable salt thereof by one pot process by reducing the novel amide compound of formula II using reducing agent selected from borane compounds and metal hydrides such as BH3-THF, BH3-DMS, BH3-amine, BH3-lewis acid, BH3-PPh3 and the like, lithium aluminium hydride, sodium borohydride in the presence of additives like iodine, sulfuric acid or lewis acids along with mineral acid like hydrochloric acid, hence without isolating the base. The reaction can be conducted in the presence or absence of an organic solvent thus affording the salt in high yield and purity.
Specific compound arising from the amine derivative of formula I include cinacalcet hydrochloride of formula-Ill,
(Formula Reomoved)In a preferred embodiment of the present invention, cinacalcet hydrochloride of formula III may be prepared by the scheme as shown below:
(Formula Reomoved)wherein R" andXare as described above.
According to the scheme, the starting material 3-trifluoromethylaniline is diazotized and reacted with alkene derivative of formula CH2=CHR" to afford a compound of formula XII. (Formula Reomoved)wherein R" is as described above, and X=halo selected from chloro, bromo, the like.
Specifically, 3-trifluoromethylaniline is reacted with alkene derivative of formula CH2=:CHR" in the presence of diazotization reagent, dilute mineral acid and catalyst at a temperature of about -20 to 20°C. The mineral acid can be selected from hydrochloric acid,
hydrobromic acid, and the like and diazotization reagent is selected from amongst, but not limited to nitrous acids, alkyl nitrites, nitrogen dioxide, nitrosyl chloride, and the like. Preferably sodium nitrite is employed. The catalyst can be selected from amongst, but not limited to copper (II) oxide, copper (I) oxide, and the like. After initiation of the reaction, the reaction mass is stirred for few hours at ambient temperature and it takes 10-20 hours for completion of reaction. Thereafter the product is extracted with a suitable organic solvent such as toluene to obtain a compound of formula XII.
The compound of formula XII is then transformed to yet another key intermediate, m-
trifluoromethylhydrocinnamic acid of formula XIII by several methods. (Formula Reomoved)According to one embodiment of the present invention, the compound of formula XII is
hydrolyzed to corresponding acid analogue of formula XIV, (Formula Reomoved)
wherein X is as defined above,
by acid or basic hydrolysis, followed by dehydrohalogenation to afford m-trifluoromethylhydrocinnamic acid of formula XIII.
Specifically, compound of formula XII {wherein R" is CN, COOR'; X is halo) is hydrolyzed to corresponding acid analogue by refluxing the compound of formula XII and a suitable acid preferably selected from hydrochloric acid, hydrobromic acid and the like for a period of 2-10 hours, cooling the reaction mixture to 25-30°C followed by extraction with a suitable organic solvent preferably toluene to afford an acid compound of formula XIV.
The acid compound of formula XIV is then dehydrohalogenated by the methods well known in art, preferably by treatment with zinc in the presence of aqueous acetic acid at a temperature of about room temperature to -118°C. After completion of reaction, acetic acid is distilled off completely and reaction mass is cooled to room temperature and then treated with chilled concentrated inorganic acid, preferably selected from hydrochloric acid, hydrobromic acid and the like to afford m-trifluoromethylhydrocinnamic acid of formula XIII.
In the preferred embodiment of the present invention, acid analogue of compound of formula XII can optionally be isolated and can optionally be purified by giving base-acid treatment in a suitable inert solvent selected from amongst, but not limited to toluene, isopropylether, methyltertiarybutylether, ethyl benzene and xylene. Preferably toluene is employed.
According to another embodiment of the present invention, the compound of formula XII is first hydrodehalogenated to form intermediate of formula XV, (Formula Reomoved)
wherein R " is as defined above,
followed by acidic or basic hydrolysis to afford a compound of formula XIII by the methods reported in prior art or to be exemplified in the present invention.
Acid employed for hydrolysis can be selected from amongst inorganic acids like hydrochloric acid, hydrobromic acid and the like; organic acid selected from methylsufonic acid, p-tolylsulfonic acid, the like or mixtures thereof, whereas base can be selected from alkali metal hydroxide, alkali earth metal hydroxide. Preferably sodium hydroxide, potassium hydroxide and the like can be employed. Hydrolysis can be done in the presence of suitable solvent selected from CrC4 alcohols, monoethylene glycol and the like. Reaction can be performed at a temperature of about room temperature to reflux temperature.
According to yet another embodiment of the present invention, the compound of formula XII can be transformed to m-trifluoromethylhydrocinnamic acid of formula XIII via another intermediate, namely m-trifluoromethylcinnamic acid of formula XVI or salt thereof. (Formula Reomoved)
Specifically, the compound of formula XII is first hydrolysed to compound of formula XIV and thereafter converted to cinnamic acid analogue of formula XVI. The salt of compound of formula XVI include lithium, sodium, potassium, trialkylammonium and the like. Generally acid compound of formula XIV is treated with base in suitable solvent optionally in the presence of a phase transfer catalyst. The suitable solvent can be selected from water, isopropyl alcohol, tetrahydrofuran, ethyl nitrile, toluene, cyclohexane, methylenedichloride, the like or mixtures thereof and phase transfer catalyst can be selected from tetraalkyl ammonium halide, triethylamine, trialkyl aryl halide, preferably benzyltriethylammonium chloride is employed. The base is selected from tertiary organic bases like trialkyl amines, l,8-diazabicyclo[5.4.0]undec-7-ene; aqueous alkali metal hydroxide, alkali metal carbonate or bicarbonates, alkali metal being selected from lithium, sodium, potassium, and the like; preferably sodium hydroxide, sodium carbonate are employed. The reaction is accomplished at temperature of 40-60°C followed by the removal of solvent under vacuo. Thereafter reaction mass is diluted with water at 0°C and acidified with mineral acid preferably hydrochloric acid. The resulting solid is filtered, washed, and dried to afford m-trifluoromethylcinnamic acid of the formula XVI.
Further, compound of formula XVI is then reduced to m-trifluoromethylhydrocinnamic acid of formula XIII by the methods well known in art. In the preferred embodiment, reduction is performed by catalytic reduction, employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium oxide, and the like in the presence of hydrogen transfering agents like formic acid, ammonium formate, cyclohexene and dihydrogen.
The conversion of the compound of formula XII to m-trifluoromethylhydrocinnamic acia 01 formula XIII can also be performed by other methods known per se or as exemplified in the context of the present invention.
Yet another embodiment of the present invention provides a process for the conversion of compound of formula XIII to novel and key intermediate of formula VIII, (Formula Reomoved)
wherein X is hydrogen, halo selected from chloro, bromo and the like
which comprises introducing an acyl group of formula IVa, (Formula Reomoved)
wherein X = H or halo, wherein halo can be chloro, bromo or the like;
into the amino group of molecule of formula Va or a salt thereof
(Formula Reomoved)Typically, the conversion of compound of formula XIII to novel and key intermediate of formula VIII can be effected by initially converting m-trifluoromethylhydrocinnamic acid of formula XIII to its reactive derivative like acid halide, inorganic or organic acid anhydride, mixed acid anhydride, cyclic carboxy-anhydride, active amide or ester by reaction with a reagent like phosphorous trihalide, phosphorous pentahalide, thionyl halide, organic acid halide like acetyl chloride, pivaolyl chloride, alkyl chloroform ate, lewis acid like boric acid, and the like.
Preferably m-trifluoromethylhydrocinnamic acid of formula XIII is treated with thionyl chloride in the presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100°C followed by the removal of solvent and thionyl chloride by distillation to afford the corresponding acid chloride analogue.
The reactive derivative preferably acid chloride derivative of compound of formula XIII so formed is made to react with R-(+)-l(l-naphthyl)ethylamine of formula Va to afford amide derivative of formula Villa, which is novel and key intermediate in the preparation of cinacalcet and therefore represents further part of the invention. (Formula Reomoved)
Formula Villa
Alternatively the amide compound of formula II may be prepared by acylation of different intermediates as discussed. The acylation reaction can be performed by following the general conditions of acylation as discussed above. Specifically, the functional derivative of compound of formula XIV in the suitable organic solvent is added to a suitable aqueous base, with or without the presence of catalytic amount of catalyst like 4-dimethylaminopyridine, followed by the addition of R-(+)-l(l-naphthyl)ethylamine in the suitable organic solvent at a temperature of-10 to 10°C and constant stirred for few hours at ambient temperature, washed with aqueous sodium carbonate, and dried to afford (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-propionamide of the formula Villa in high yield and purity.
The organic solvent can be selected from water, toluene, ethyl benzene, xylene, isopropylether, acetone, tetrahydrofuran, dioxane, acetonitrile, chloroform, dichloromethane, dichloroethylene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether, toluene, and the like. Base can be selected from organic bases like pyridine, triethylamine, N,N-dimethylaniline, or inorganic bases like alkali bicarbonate, carbonates like sodium hydrogen carbonate and the like.
In yet another embodiment of the present invention, compound of formula XIV can directly be acylated with R-(+)-l(l-naphthyl)ethylamine under general acylation conditions as described in present invention to give represents further part of the invention, (Formula Reomoved)
wherein X halo selected from chloro, bromo, iodo,
and converted to amide derivative of formula Villa by dehydrohalogenation. Typically compound of formula Vlllb is hydrodehalogenated by reacting the same with aqueous acetic acid and adding zinc powder to it at about ambient temperature. Reaction mass is then heated to 50-70°C for few hours. Acetic acid is removed by the conventional methods like distillation. To the reaction mass, inert solvent preferably toluene followed by concentrated mineral acid preferably hydrochloric acid is added with constant stirring. The organic layer is separated, washed with water and solvent removed under vacuum to afford amide derivative of formula Villa that can further be converted to cinacalcet of formula Ilia and pharmaceutical ly acceptable salt thereof. (Formula Reomoved)
Reduction of amide derivative of formula Villa to cinacalcet hydrochloride of formula III can be effected by stirring a solution of amide derivative of formula Villa in a suitable solvent selected from tetrahydrofuran, dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether, methyltertiarybytylether at a temperature of below 10°C, in the presence of suitable reducing agent, followed by heating to a temperature of 50-70°C with continuous stirring for few hours. Reducing agent can be selected from metallic hydride complexes such as lithium aluminum hydride, diethyl aluminum hydride, sodium aluminum hydride, sodium
borohydride, with additives such as iodine, sulfuric acid, lewis acids; or borane complexes selected from amongst borane-tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane-triphenylphosphine and the like. Solvent is distilled off under vacuo followed by the addition of C1-C2 alcohol at a temperature of below 5°C with stirring for few minutes. Alcohol is then distilled off under vacuo followed by the addition of mineral acid specifically hydrochloric acid at 0-5°C. This is followed by stirring at about ambient temperature for few hours and further heating to 80-95°C for few hours. The reaction mass is then cooled to ambient temperature, filtered, washed with water and dried to afford cinacalcet hydrochloride of formula III in high purity and yield.
In yet another embodiment of the present reaction, m-trifluoromethylcinnamic acid of
formula XVI can directly be acylated with R-(+)-l(l-naphthyl)ethylamine under general
acylation conditions as described in present invention to give yet another novel in
intermediate, (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide
having formula XVII, that represents further part of the invention, (Formula Reomoved)
Compound of formula XVII is then reduced using suitable reducing agent to cinacalcet hydrochloride of formula III.
Typically, a solution of (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acryl amide having formula XVII in a suitable solvent is cooled to a temperature of below 5°C with constant stirring. This is followed by the addition of reducing agent selected from amongst borane complexes selected from amongst borane-tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane-triphenylphosphine and the like, followed by heating a temperature of 50-70°C. Solvent can be selected from toluene, xylene, ethyl benzene, isopropyl ether, methyl tertiary butyl ether. Solvent is then removed by distillation under vacuum followed by the addition of alcoholic solvent preferably methanol at a

temperature of below 5°C with constant stirring. Solvent is then distilled off under vacuo followed by addition of mineral salt preferably hydrochloric acid at a temperature of below 5°C, followed by heating at a temperature of 85-90°C. The reaction mass is then extracted with chlorinated solvent preferably dichloromethane and concentrated in vacuum to afford cinacalcet hydrochloride in high yield and purity.
In the specific embodiment of the present invention, (R)-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-propionamide of the formula Villa can be converted to cinacalcet acid addition salt in one step by suspending the amide intermediate of formula Villa in a suitable solvent, cooling to a temperature of below 10°C under constant stirring followed by the addition of suitable reducing agent with heating to 60-65°C. Reducing agent can be selected from the one mentioned earlier, preferably borane complexes selected from amongst borane-tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane-triphenylphosphine and the like are used. Solvent can be selected from amongst, but not limited to tetrahydrofuran, dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether, methyltertiarybutylether, the like and mixtures thereof. Solvent is distilled off under vacuo followed by the addition of alcoholic solvent preferably methanol at a temperature of 0°C with constant stirring for few minutes. Alcoholic solvent is distilled off under vacuo followed by the addition of suitable acid preferably hydrochloric acid at a temperature of below 5°C, followed by heating at 80-100°C. The reaction mass is then cooled to ambient temperature, filtered, washed with water and dried to afford cinacalcet acid addition salt, preferably cinacalcet hydrochloride in high yield and purity.

one of mass spectra (MS), infra-red spectroscopy (IR), 'H or 13C Nuclear magnetic resonance
Novel amide intermediates encompassed by the invention may be characterized by at least one of mass spectra (MS), infra-red spectroscopy (IR), 'H or spectroscopy (NMR) or differential scan calorimetry (DSC).
Cinacalcet can also be isolated as cinacalcet free base but it is usually more convenient to isolate cinacalcet as acid addition salt. Cinacalcet can be converted to pharmaceutically acceptable salt thereof by the methods well known in art. Generically, pharmaceutically acceptable salts can be prepared by dissolving the free base form of cinacalcet in a suitable

solvent, containing the appropriate acid and isolating the salt there from. In yet another embodiment of the present invention, the reaction can also be effectively performed in the absence of solvents. In yet another embodiment, cinacalcet free base can be converted to its hydrochloride salt by refluxing a mixture of cinacalcet free base and ammonium chloride in alcoholic solvent like methanol for a time sufficient to convert to its hydrochloride salt.
Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. Preferably, cinacalcet is isolated as corresponding hydrochloride.
According to yet another embodiment of the present invention, the acid addition salts of the cinacalcet may be converted to the corresponding free base by treating with a suitable inorganic base, such as carbonate, bicarbonate or hydroxide, typically in the presence of a solvent, and at a temperature of between about 10°C and 50°C. The free base form is isolated by conventional means, such as extraction with an organic solvent. The solvent can be selected from ethers like isopropyl ether, methyl tertiary butyl ether, xylene, ethyl benzene, isopropyl ether and halides like dichloromethane, chloroform, dichloroethane, carbon tetrachloride, and the like.
The desired compound and intermediates prepared as such can be separated and purified by various means known per se such as, for example, concentration, conversion of liquid properties, transfer to another solvent and extraction with a solvent, crystallization, centrifuge, recrystallization, fractional distillation, chromatography, and the like.
In the preferred embodiment of the present invention, cinacalcet hydrochloride can optionally be purified by refluxing cinacalcet hydrochloride in a suitable organic solvent selected from
amongst, but not limited to nitriles, methyl isobutyl ketone, CrC4 alcohol, ethyl acetate, dimethyl acetamide, diethyl ether, toluene, xylene, isopropyl ether, dioxane, dimethylformamide, dimethylsulfoxide, N-methyl pyrolidine, hexane, tetrahydrofuran, methylene dichloride, chloroform, methyl tertiary butyl ether and mixtures thereof for a time sufficient to obtain highly pure cinacalcet hydrochloride having purity greater than 99% by HPLC.
The present process has the advantage of being regio-selective, involving relatively mild reaction conditions and no racemization of the chiral starting material.
The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.
EXAMPLES
Example 1; Preparation of m-trifluoromethyl-a-chlorohydrocinnarnonitrile
Concentrated hydrochloric acid (129ml) was added to the chilled solution of m-trifluoromethyl aniline(lOOg) and demineralized water(176 ml) followed by the addition of acrylonitrile (121 g) at 0-5 °C along with chilled aqueous sodium nitrite solution (45.1 g in 65 ml of water). Allowed it to stir at 0-5°C for 20 minutes and then at 20°C for 1 hour. The reaction mixture was further cooled to 0-5°C and copper (I) oxide (6 g )was added at 0-5°C. The reaction mixture was further stirred for 2 hours at 0-5 °C and at room temperature for 15 hours. After completion of reaction, toluene was added, and the layers were separated. The aqueous layer was extracted twice with toluene and combined organic layer was washed with demineralized water, and dried over sodium sulphate. The solvent was distilled under vacuum at 50°C to yield 144 g of the title compound.
Example 2: Preparation of m-trifluoromethyl-a-chlorohydrocinnamic acid
m-Trifluoromethyl-a-chlorohydrocinnamonitrile(50g) was treated with concentrated hydrochloric acid (200ml )at room temperature and thereafter heated at 80-85°C for 4 hours.
The reaction mixture was then cooled to room temperature and toluene was added with constant stirring and layers were separated. The aqueous layer was extracted with toluene and combined organic layer washed with demineralized water. To the toluene layer, 10% sodium bicarbonate ( 330ml) was added and stirred, the layers were separated. The aqueous layer was cooled to 0-5°C and chilled concentrated hydrochloric acid was added till pH of about 1. To the reaction mass, toluene was added, and layers were separated, washed with demineralized water and dried over sodium sulfate. The organic layer was distilled under vacuum at 50°C to give 36 g of the title compound.
Example 3: Preparation of m-trifluoronicthylhvdrocinnamic acid
To m-trifluoromethyl-a-chlorohydrocinnamic acid (30 g) was added aqueous acetic acid (126 ml) and stirred at room temperature. Zinc powder (23.2 g) was added and the mixture was stirred at room temperature for half an hour and at 35°C for further half an hour. Acetic acid was distilled off completely at 85-90°C at 2mm Hg and reaction mass was cooled to room temperature and treated with chilled concentrated hydrochloric acid (50 ml). To the reaction mass, toluene was added, stirred and layers were separated. The aqueous layer was extracted with toluene and combined organic layer was washed with demineralized water. To the toluene layer, 10% sodium bicarbonate was added till a pH of 9.5 and stirred, the layers were separated. The aqueous layer was cooled to 0-5°C and chilled concentrated hydrochloric acid was added till pH of about 1. The aqueous layer was extracted with toluene. The toluene layer was washed with demineralized water, dried over sodium sulfate and distilled out completely to obtain 21.7 g of the title compound.
Example 4: Preparation of m-trifluoromcthyl-a-bromohydrocinnamic acid
Concentrated hydrobromic acid (15.1ml) was added to the chilled solution of m-trifluoromethyl aniline (5g) and demineralized water(9 ml) followed by addition of acrylic acid (8.21g) at 0-5°C along with chilled aqueous sodium nitrite solution (2.3 g of sodium nitrite in 3.3 ml of water). Allowed it to stir at 0-5°C for 20 minutes and then at 20°C for 1 hour. The reaction mixture was further cooled to 0-5°C and copper (I) oxide (0.3g) was added at 0-5°C. The reaction mixture was further stirred for 2 hours at same temperature and at room temperature for further 15 hours. After completion of reaction, toluene was added, and layers were separated. The aqueous layer was extracted with toluene and combined toluene
layer was washed with demineralized water. The toluene was distilled under vacuum to afford 8 g of the title compound.
Example 5; Preparation of m-trifluoromethyl q-bromohydrocinnamonitrile
To a stirred mixture of 3-trifluoromethylaniline (250.Og, 1.55moles) and demineralized water (440ml) was added hydrobromic acid (754ml) over 1 hour at 0-5°C followed by addition of acrylonitrile (368ml) maintaining temperature 0-5°C. A solution of sodium nitrite (lllg sodium nitrite in 160ml of water) was added at same temperature and stirring was continued for 1.5 hours followed by the addition of copper(I) oxide (14.6g). The reaction mixture was initially stirred at 0-5°C for 2 hours and then at 20-25°C for 15 hours. The product was extracted with toluene (200 ml x 3). The organic extracts were combined and washed with water (500ml x2). Toluene was removed under reduced pressure to give 395g of the title compound.
Example 6: Preparation of m-trifluoromcthvl-a-bromohydrocinnamic acid
A mixture of m-trifluoromethyl-a-bromohydrocinnamonitrile(385g) and hydrochloric acid (2.3 litres) was refluxed for 7.5 hours, cooled to 25-30°C followed by extraction with toluene (500ml x3). The combined organic extracts were washed with water and concentrated under reduced pressure to afford 374g of the crude title compound. The crude product was taken in toluene (600ml) and aqueous sodium hydroxide (1.0 1, 15%) was added at 10-15°C and stirred for 15 minutes. The layers were separated and aqueous layer was washed with toluene (200ml x2), acidified with hydrochloric acid (500ml) at 10-15°C and extracted with toluene (500ml x3). The combined organic extracts were washed with water and concentrated under reduced pressure to afford the title compound which was used as such in the next step.
Example 7: Preparation of m-trifluoromethylcinnamic acid
To a suspension of m-trifluoromethyl-a-bromohydrocinnamic acid obtained in example 6, isopropanol (1.42 1) and benzyltriethylammonium chloride (10.85g), aqueous sodium hydroxide (340 ml, 56%) was added slowly. The temperature was raised to 55-60°C, stirred for 7 hours and isopropanol was removed in vacuo. Water (500ml) was added to the reaction mass, stirred and cooled to 0°C and acidified with hydrochloric acid (450ml). The solid was filtered, washed with water and dried in vacuo at 50°C to afford 204g of the title compound.
Example 8; Preparation of m-trifluoromethylhydrocinnamic acid
A suspension of m-trifluoromethylcinnamic acid (194g) isopropyl alcohol (970ml) and Pd/C (19.4g, 10%) was hydrogenated for 4 hours at 1.0 kg/cm2 hydrogen pressure. After completion of reaction, the reaction mass was filtered through hyflo bed, and concentrated in vacuo to afford 195g of the title compound.
Example 9; Preparation of methyl m-trifluoromethyl-a-bromohydrocinnamate
To a mixture of 3-trifluoromethylaniline (lOg) and demineralized water (18ml) was added hydrobromic acid (30ml) over 1 hour at 0-5°C followed by addition of methylacrylate (21ml) at 0-5°C. A solution of sodium nitrite (4.5g) in water (6.5ml) was added at above temperature and stirring continued for 1.5 hour followed by the addition of copper(I) oxide (0.6g). The reaction mixture was initially stirred at 0-5°C for 2 hour and then at 20-25°C for 15 hour. The product was extracted with toluene (50 ml x 3). The organic extracts were combined and washed with water (30ml x2). Toluene was removed under reduced pressure to give 19g of the title product.
Example 10: Preparation of methyl m-trifluoromethylhydrocinnamate
To a mixture of methyl m-trifluoromethyl-a-bromohydrocinnamate (14g), acetic acid (53ml) and demineralized water (2.8ml), was added zinc powder (4.4g) at 20-25°C. Reaction mass was then heated to 60-65°C for 4.5 hours. Acetic acid was distilled off under reduced pressure. To the residue, toluene was added followed by addition of cone, hydrochloric acid. The reaction mixture was stirred for 10 minutes and the toluene layer was separated. Toluene layer was washed with water and toluene was removed under vacuo to afford lOg of the title compound.
Example 11 Preparation of m-trifluoromethylhydrocinnamic acid
A mixture of methyl m-trifluoromethyl-hydrocinnamate(0.5g), isopropanol (2.5ml) and sodium hydroxide (0.9g) was stirred at room temperature for 6 hours. Isopropanol was distilled off, water (2ml) added and washed with isopropyl ether. Reaction mixture was then acidified with hydrochloric acid, extracted with dichloromethane, organic layer separated and concentrated in vacuo to give 0.44g of title compound.
Example 12;Preparation of m-trifluoromethylhydrocinnamonitrile
To a mixture of m-trifluoromethyl-a-bromohydrocinnamonitrile (392 g), acetic acid (1.49 1) and demineralized water (78.4 ml), was added zinc powder (138.3 g) at 20-25°C. The temperature of reaction mass was raised to 60-65°C and heated for 4.5 hours. Acetic acid was distilled off under reduced pressure. To the residue, toluene (500 ml) and cone, hydrochloric acid (500 ml) were added, stirred for 10 minutes and the layers were separated. Organic layer was washed with water and toluene was removed under vacuo to afford 249g (88.5%) of the title compound.
Example 13: Preparation of m-trifluoromethylcinnamonitrilc
To a suspension of m-trifluoromethyl-a-bromohydrocinnamonitrile (Ig), acetone (5ml) and benzyltriethylammoniumchloride (81mg), was added sodium carbonate (1.14g) and water (0.3ml). The temperature was raised to 40-45°C, stirred for 7 hours and acetone was removed in vacuo. Water (5ml) was added to the reaction mass, stirred and cooled to 0°C and acidified with hydrochloric acid. The product was extracted with isopropylether, washed with water. The solvent was concentrated in vacuo and dried to afford 0.65g of m-trifluoromethylcinnamonitrile.
Example 14:Preparation of m-trifluoromethylhydrocinnamic acid
A stirred mixture of m-trifluoromethylhydrocinnamonitrile (243.45g) and hydrochloric acid (1.2 litres) was refluxed for 4.5 hours, cooled to 25-30°C followed by extraction with toluene (500 mlx3). The combined organic extracts were washed with water and concentrated under reduced pressure to afford 250g (94%)of the title compound.
Example 15: Preparation of m-trifluoromethylhydrocinnamic acid
A mixture of m-trifluorornethylhydrocinnamonitrile (5g), demineralized water (4ml), monoethylene glycol (10ml) and sodium hydroxide (4g) was stirred at 125°C for 9 hours. Reaction mixture was acidified, extracted with toluene. Toluene was concentrated in vacuo to give 4.6g of title product.

Example 16: Preparation of (R)-N-(l-naphthalen-l-yl-ethvl)-3-(3-trifluoroniethyl-phenvD-propionamide
A mixture of m-trifluoromethylhydrocinnamic acid (5g), toluene (50ml), boric acid (7mg) and R-(+)-l(l-naphthyl)ethylamine (3.7g) was refluxed azeotropically for 12 hours and cooled to ambient temperature. The product was filtered, washed with IN-hydrochloric acid and water and dried to afford 8.5g of (R)-N-(l-Naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-propionamide.
Melting point: 116- 119°C
MS (m/z): 372.2[M+I]
1R (KBr) (vmax, cm'1): 3301(N-H stretching), 1643(C=O stretching), 1556(aromatic C=C
stretching).
'H NMR (CDC13) (Sppm): 7.2-8.0(11H, m, Ar-H), 5.84(1H, m, C-H), 5.84(1H, m, N-H),
3.00(2H, m, CH2), 2.39(2H, t, CH2), 1.54(3H, m, CH3).
I3C-NMR (CDC13) (ppm): 20.57, 31.27, 37.87, 44.60, 122.49, 122.82, 123.10, 123.30,
124.99, 125.17, 125.53, 125.89, 126.56, 128.36, 128.80, 128.89, 131.02, 131.94, 133.88,
138.08, 141.72, 170.38, 130.52.
Example 17; Preparation of (R)-A^l-naphthvlen-l-vlethvr)-3-[3[(trifluoromethyl-phcnyll propionamide
A mixture of m-trifluoromethylhydrocinnamic acid (5g) in toluene (25ml) and thionyl chloride (2.5ml) was initially stirred at room temperature for half an hour and then heated at 100-110°C for 4-5 hours. The solvent was distilled and reaction mass was cooled to room temperature and to this methylenechloride (20ml) was added. In a separate flask R-(+)-l(l-naphthyl)ethylamine (3.9g) was taken in methylenedichloride(25 ml), cooled to 0-5 °C and triethylamine (4.8 ml) was added at 0-5°C. To this chilled solution, acid chloride solution in methylenedichloride prepared above, was added at 0-5°C and stirred. After completion of reaction, chilled concentrated hydrochloric acid (20 ml) was added, stirred and the layers were separated. The organic layer was washed with water and solvent was distilled to isolate 7.96 g of (R)-N-(l-naphthylen-l-ylethyl)-3-[3[(trifluoromethyl- phenyl] propionamide.
Example 18: Preparation of (R)-N-(l-naphthalen-l-vl-ethyl)-3-(3-trifluoromethyi-phenyD-propionamide
A mixture of m-trifluoromethylhydrocinnamic acid (240g, 1.1 mole), toluene (1.2 I) and thionylchloride (120ml) was heated to 85-90°C for 4 hours. Toluene and thionylchloride were distilled off under reduced pressure. After complete removal of thionylchloride, methyl-tertiarybutylether (1.1 litre) was added to the acid chloride at 20-25°C. This Acid chloride solution in methyltertiarybutylether was added to a prestirred mixture of aqueous sodium carbonate (199g in 800ml of water), R-(+)-l(l-naphthyl)ethylamine (179g) and methyltertiarybutyl- ether (1.63 1) at 5 to 10°C over of 30 minutes. Stirring was continued for 1.0 hour at 20-25°C, methyltertiarybutylether layer was separated, washed with aqueous sodium carbonate, IN hydrochloric acid (720ml) and demineralized water (720ml). The organic layer was distilled under vacuo and dried in oven at 45-50°C to afford 350g of the title compound.
Example 19: Preparation of (R)-2-brotno-N-(l-naphthalen-l-vl-ethvl)-3-(3-trifluoromethvl-phenyD-propionamide
A mixture of m-trifluoromethyl-a-bromohydrocinnamic acid (lOg), toluene (50 ml ) and thionyl chloride (3.6ml) was heated to 85-90°C for 4 hours. Toluene and thionylchloride were distilled off under reduced pressure. After complete removal of thionylchloride, methyltertiarybutylether (75ml) was added at 20-25°C. This acid chloride solution in methyltertiarybutylether was added to a prestirred mixture of aqueous sodium carbonate (6.1g+24ml), R-(+)-l(l-naphthyl)ethylamine (4.6g) and methyltertiarybutylether (75ml) at 5 to 10°C over of 30 minutes. Stirring was continued for 1 hour at 20-25°C, methyltertiarybutylether layer separated, washed with aqueous sodium carbonate, IN hydrochloric acid and demineralized water. The organic layer was distilled under vacuo and dried in oven at 45 - 50°C to afford 6.8g of the title product.
Melting point: 122.5-124.2°C
MS(m/z): 333 [M-l]
IR (KBr) (umax, cm'1): 3290.52, 1651.75, 1612.7, 1539.57, 1450.64, 1348.8, 1332, 1215.48,
1180.94, 1119.57, 968.85, 801.17, 776.49, 697.52.
'H NMR (CDC13) (5ppm) : 7.2-8.3 (1 lH,m), 6.43 (1H, m), 5.87 (1H, m), 4.48 (1H, m), 2.65 (1H, m), 1.63(3H,m).
Example 20: Preparation of (R)-N-(l-Naphthalen-l-yl-ethy!)-3-(3-trifluoronicthvl-phenvD-propionamide
Zinc powder (0.22g) was added to a mixture of (R)-2-bromo-N-(l-naphthalen-l-yl-ethyl)-3-(3-trifIuoromethyl-phenyl)-propionamide (0.5g), acetic acid (2ml) and demineralized water (O.lml) at 20-25°C. Reaction mass was then heated at 60-65°C for 4.5 hours. Acetic acid was distilled off under reduced pressure. To the residue, toluene and cone, hydrochloric acid were added, stirred for 10 minutes and the layers were separated. Organic layer was washed with water and toluene was removed under vacuo to afford 0.4g of the title compound.
Example 21: Preparation of Cinacalcet hydrochloride
To a solution of (R)-N-(l-naphthalen-l-yl-ethyI)-3-(3-trifluoromethyl-phenyl)-propionamide (350g) in tetrahydrofuran (1.4 1) at 0-5°C, borane dimethylsulphide complex (179 ml) was added, and heated at 60-65°C for 4 hours. Tetrahydrofuran was distilled off under vacuo. Methanol (1.05 1) was added at 0°C and stirred for another 30 minutes. Methanol was distilled off under vacuo and the residue was treated with hydrochloric acid (2.1 1) at 0-5°C. The reaction mixture was stirred at 25-30°C for 2.0 hours and further at 85-90°C for 2.0 hours. The reaction mass was then cooled to 25-30°C, filtered, washed with water and dried to afford 37Ig of the title compound. The product so obtained was recrystallized with acetonitrile to afford pure cinacalcet hydrochloride having purity of 99.67% by HPLC.
Example 22: Preparation of (R)-N-(l-naphthalen-l-vl-ethvl)-3-(3-trifluoromcthvl-phcnvl)-acrvlaniide
A mixture of m-trifluoromethylcinnamic acid (5g), toluene (25ml ) and thionyl chloride (2.5ml) was heated to 85-90°C for 4 hours. Toluene and thionyl chloride were distilled off under reduced pressure. After complete removal of thionyl chloride, methyl tertiary butyl ether (25ml) was added to the acid chloride at 20-25°C. This solution was added to a prestirred mixture of aqueous sodium carbonate (4.1g + 16ml), R-(+)-l(l-naphthyl)ethylamine (3.76g) and methyl tertiary butyl ether (25ml) at 5 to 10°C over of 30 minutes. Stirring was continued for 1.0 hour at 20-25°C, methyl tertiary butyl ether layer
separated, washed with aqueous sodium carbonate, IN hydrochloric acid and demineralized water. The organic layer was distilled under vacuo and dried in oven at 45-50°C to afford 7.5g of the title compound.
Melting point: 177-180°C
MS (m/z): 333 [M-l]
IR (KBr) (i>milx, cm'1): 3290.52, 1651.75, 1612.7, 1539.57, 1450.64, 1348.8, 1332, 1215.48,
1180.94, 1119.57, 968.85, 801.17, 776.49, 697.52.
'H NMR (CDC13) (6ppm): 7.45-8.2 (1 lH,m), 7.7 (1H, d), 6.4 (1H, d), 6.08 (1H, m), 5.84
(1H, m), 1.76 (3H,d).
Example 23: Preparation of Cinacalcet hydrochloride
To a cooled solution of the (R)- N-(l-naphthalen-l-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide (5g) in tetrahydrofuran (25ml), borane dimethylsulphide complex (4.05g) was added at 0-5 °C. The temperature of reaction mixture was raised to 60-65°C and stirred for 4 hour. Tetrahydrofuran was distilled off under vacuo followed by addition of methanol (25ml) at 0°C and stirring for another 30 minutes. Methanol was distilled off under vacuo followed by addition of hydrochloric acid at 0-5°C, stirring at 25-30°C for 2.0 hours and further heating to 85-90°C for 2.0 hours. The reaction mass was extracted with dichloromethane and concentrated in vacuo to afford 4.2g of the compound. The crude material was purified with acetonitrile to afford pure cinacalcet hydrochloride.
Example 24: Preparation of Cinacalcet free base
To a stirred suspension of Cinacalcet hydrochloride (crude, 250g) in isopropylether (1.25 1) at 25°C was added 15% aqueous sodium carbonate solution till a pH of 9.5 at 25°C in duration of 15 minutes and stirred for 2.0 hours. Stirring was stopped and the layers separated. The organic layer was washed with water (250ml x2), dried over sodium sulfate, and distilled in vacuo to afford 222g of cinacalcet free base.

WE CLAIM
1. A process for the preparation of cinacalcet hydrochloride of formula III,
(Formula Removed)
which comprises reducing amide intermediate of formula Villa or a salt thereof, (Formula Removed)

using a suitable reducing agent at a temperature of below 10°C to reflux temperature of solvent, and isolating cinacalcet hydrochloride.
2. The process according to claim 1, wherein solvent is selected from tetrahydrofuran,
dioxane, aromatic solvents, toluene, ethyl benzene, xylene, isopropyl ether,
methyltertiarybytylether and the like.
3. The process according to claim 1, wherein suitable reducing agent is selected form
borane complex, metal hydrides with additives, or catalysts such as Raney nickel,
platinum oxide, palladium-carbon, ruthenium-carbon, rhodium-carbon, copper-chromium
oxide, and the like employing nascent hydrogen obtained by the co-existence of metals
such as sodium, sodium amalgam, aluminum amalgam etc. and water, alcohols.
4. The process according to claim 3, wherein borane complex is selected from borane-
tetrahydrofuran, borane-dimethylsulfoxide, borane-amine, borane-lewis acid, borane-
triphenylphosphine and the like
5. The process according to claim 3, wherein metal hydride with additives is selected from
lithium alumuinium hydride, diethyl aluminium hydride, sodium aluminium hydride,
sodium borohydride, with additives such as iodine, sulfuric acid and lewis acids.
6. A process for the preparation of novel amide intermediate of formula VIII or a salt thereof, (Formula Removed)
Formula-VIII

wherein X=H or halo selected from chloro, bromo and the like
which comprises introducing an acyl group of formula IVa, (Formula Removed)

Formula IVa
wherein X = H or halo, wherein halo can be chloro, bromo or the like; into the amino group of molecule of formula Va or a salt thereof.
(Formula Removed)
Formula Va

7. A process for the preparation of amide intermediate of formula Villa or a salt thereof,
(Formula Removed)
from a compound of formula XII,
(Formula Removed)

wherein R" can be selected from CN, CONR1 R2, COOR', wherein R' is hydrogen or an alkyl group, R and R2 can be independently selected from H or lower alkyl group, while X is selected from H, halo, provided both R' and X cannot be H simultaneously.
8. The process according to claim 7, wherein compound of formula XII is converted to compound of formula Villa which comprises:
a) hydrolysing the compound of formula XII with a suitable acid or base to prepare a
compound of formula XIV, (Formula Removed)
b) treating compound of formula XIV with a suitable base like organic or inorganic base, in
the presence of a suitable solvent selected from water, isopropyl alcohol, tetrahydrofuran,
ethyl nitrile, toluene, cyclohexane, methylenedichloride, the like or mixtures thereof and
optionally a phase transfer catalyst selected from tetraalkyl ammonium halide, trialkyl
aryl halide to prepare m-trifluoromethylcinnamic acid of formula XVI or salt thereof, ,COOH(Formula Removed)
Formula XVI
c) reducing the compound of formula XVI with suitable reducing agent to prepare m-
trifluoromethylhydrocinnamic acid of formula (Formula Removed)
Formula-XIII
d) treating m-trifluoromethylhydrocinnamic acid of formula XIII with suitable reagent to
prepare the reactive derivative like acid halide, anhydride, active amide or ester in the
presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100° C,
e) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in
suitable solvent in the presence of base to afford a compound of formula Villa.
9. A process according to claim 8, wherein reduction is performed by catalytic reduction,
employing catalysts such as Raney nickel, platinum oxide, palladium-carbon, ruthenium-
carbon, rhodium-carbon, copper-chromium oxide, and the like in the presence of
hydrogen transfering agents like formic acid, ammonium formate, cyclohexene and
di hydrogen.
10. The process according to claim 7, wherein compound of formula XII is converted to
compound of formula Villa which comprises:
a) hydrolysing compound of formula XII with suitable acid or base to prepare a compound
of formula XIV, (Formula Removed)
Formula-XIV
b) treating compound of formula XIV with a suitable reagent to prepare the reactive
derivative like acid halide, anhydride, active amide or ester in the presence of an inert
solvent like toluene, ethyl benzene and xylene at 80-100° C,
condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in a
suitable solvent in the presence of base to prepare a compound of formula VHIb, (Formula Removed)
Formula-VIIIb
CF3 wherein X=halo selected from chloro, brotno and the like.
d) hydrodehalogenating the resulting compound of formula VHIb to prepare compound of formula Villa.
11. The process according to claim 7, wherein compound of formula XII is converted to formula Villa which comprises:
a) hydrodehalogenating compound of formula XII to prepare a compound of formula XV,

(Formula Removed)
b) hydrolysing compound of formula XV with suitable acid or base to prepare m-
trifluoromethylhydrocinnamic acid of formula XIII,
c) treating m-trifluoromethylhydrocinnamic acid of formula XIII with a suitable reagent to
prepare the reactive derivative like acid halide, anhydride, active amide or ester in the
presence of an inert solvent like toluene, ethyl benzene and xylene at 80-100° C,
d) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in a
suitable organic solvent in the presence of base at a temperature of -10 to 10°C, to
prepare a compound of formula Villa.

12. A process according to claims 8, 10, and 11, wherein suitable reagent to prepare reactive
derivative of m-trifluoromethylhydrocinnamic acid of formula XIII is selected from
phosphorous trihalide, phosphorous pentahalide, thionyl halide; organic acid halide like
acetyl chloride, pivaolyl chloride, alkyl chloroformate, lewis acid, boric acid, the like.
13. A process according to claims 8, 10 and 11, wherein acid used during hydrolysis is
selected from inorganic acids like hydrochloric acid, hydrobromic acid and the like;
organic acid like methylsufonic acid, p-tolylsulfonic acid, the like or mixtures thereof,
whereas base used during hydrolysis is selected from alkali metal hydroxide, alkali earth
metal hydroxide, organic bases like pyridine, triethylamine, W, W-dimethylaniline.
14. The process according to claims 8, 10 and 11, wherein the hydrodehalogenation is
performed using suitable reagent selected from sodium dithionite, zinc-acetic acid, zinc-
potassium iodide, or magnesium, catalytic dehydrogenation, metal catalyst selected from
platinum, ruthenium, osmium, iridium, and especially palladium, raney-nickel, along
with a suitable solvent chosen from water, alcohol having CrC4 alkyl group,
tetrahydrofuran, toluene, xylene, ethyl acetate, hexane, heptane, isopropylether, dioxane,
the like and mixtures thereof.
15. The process according to claims 8, 10 and 11, wherein the solvent used during
condensation of reactive derivative of compound of formula XIII with R-(+)-l(l-
naphthyl)ethylamine is selected from water, acetone, tetrahydrofuran, dioxane,
acetonitrile, chloroform, dichloromethane, dichloroethylene, dimethylformamide,
dimethylacetamide, dimethylsulfoxide, methyltertiarybutylether and the like; whereas
base is selected from pyridine, triethylamine, 7V,./V-dimethylaniline, or inorganic bases
like alkali metal bicarbonates and carbonates and the like.
16. The process for the preparation of cinacalcet hydrochloride of formula III,
(Formula Removed)
which comprises:
a) diazotizing 3-trifluoromethyl-phenylamine in the presence of sodium nitrate, suitable
catalyst selected from copper (II) oxide, copper (I) oxide and an acid preferably
hydrochloric acid, hydrobromic acid and the like,
b) reacting the same with alkene derivative of formula CHa=CHR", wherein R" is as
described above, to afford a compound of formula XII,
(Formula Removed)c) converting the same to m-trifluoromethyl hydrocinnamic acid of formula XIII,
(Formula Removed)converting m-trifluoromethyl hydrocinnamic acid of formula XIII to reactive derivative
like acid halide, anhydride, active amide or ester in the presence of an inert solvent like
toluene, ethyl benzene and xylene at 80-100° C,
d) condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in the
presence of suitable solvent in the presence of a base at a temperature of-10 to 10°C to
afford a compound of formula Villa,
(Formula Removed)
f) reducing the same using suitable reducing agent at a temperature of below 10°C to reflux
temperature of solvent,
g) isolating cinacalcet hydrochloride,
h) optionally purifying cinacalcet hydrochloride with a suitable solvent selected from nitrile, methyl isobutyl ketone, Ci-C4 alcohol, ethyl acetate, dimethyl acetamide, diethyl ether, toluene, xylene, isopropyl ether, dioxane, dimethylformamide, dimethylsulfoxide, N-methyl pyrolidine, hexane, tetrahydrofuran, methylene dichloride, chloroform, methyl tertiary butyl ether and mixtures thereof.
17. A process for the preparation of cinacalcet hydrochloride of formula III,
(Formula Removed)
which comprises:
converting compound of formula XVI to reactive derivative like acid halide, anhydride,
active amide or ester in the presence of an inert solvent like toluene, ethyl benzene and
xyleneat 80-100°C,
condensing the resulting reactive derivative with R-(+)-l(l-naphthyl)ethylamine in a
suitable solvent in the presence of base at a temperature of -10 to 10°C to prepare a
compound of formula XVII, (Formula Removed)
c) reducing the resulting compound of formula XVII in the presence of a suitable solvent,
and
d) isolating cinacalcet hydrochloride.
18. An amide intermediate of formula Villa, or its salts including solvates, isomers, hydrates and enantiomers thereof
(Formula Removed)
19. An amide intermediate of formula VHIb or its salts including solvates, isomers, hydrates and enantiomers thereof. (Formula Removed)wherein X is hydrogen, halo like chloro, bromo or iodo.
20. An amide intermediate of formula XVII, or its salts including solvates, isomers, hydrates and enantiomers thereof.
(Formula Removed)