WO2010010359A2

WO2010010359A2 - A process for the preparation of cinacalcet and its salts

Info

Publication number: WO2010010359A2
Application number: PCT/GB2009/001835
Authority: WO
Inventors: Dharmaraj Ramachandra Rao; Rajendra Narayanrao Kankan; Dilip Birari
Original assignee: CILPA Ltd
Current assignee: CILPA Ltd
Priority date: 2008-07-24
Filing date: 2009-07-23
Publication date: 2010-01-28
Anticipated expiration: 2011-01-24
Also published as: WO2010010359A3

Abstract

A process for preparing (cinacalcet) α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine (formula I): or a pharmaceutically acceptable salt thereof which comprises: a) reacting 1-acetonaphthone with an alkyl amine or a substituted or non-substituted aralkyl amine in presence of a suitable solvent to form imine compound (formula III), which on reduction using suitable reducing agent yields N-substituted naphthyl ethyl amine (formula IV). b) Optionally resolving the N-substituted naphthyl ethyl amine (formula (IV) into its corresponding (R) or (S) isomer (formula IVa and IVb). c) Further reacting the (R,S) or (R) or (S)-N-substituted naphthyl ethyl amine (formula IV, IVa, or IVb) with trifluoromethyl aryl alkyl compound (formula V) in presence of a base and in a suitable solvent to form an intermediate corresponding to (R5S), (R) or (S)-N-substituted- methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (N-substituted- cinacalcet) (formula VI, Via or VIb). d) Optionally resolving (R,S)-N-substituted cinacalcet (formula VI) into its corresponding (R) and (S) isomers (formula Via or VIb). e) Converting (R5S) or (R) or (S)-N-substituted-cinacalcet (formula VI, Via or VIb) to the corresponding (R5S) or (R) or (S)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine (cinacalcet) (formula, I5 Ia or Ib)) by dealkylation or debenzylation, f) Optionally resolving (R,S)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine (cincacalcet, formula I) into (R) and (S)-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (formula Ia and Ib) using a suitable resolving agent.

Description

A Process for the preparation of cinacalcet and its salts

Field of the Invention

The present invention relates to novel processes for the preparation of α-Methyl-N-[3-[3- (1xifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine and its pharmaceutically acceptable salts.

Background of the Invention α-Methyl-N- [3 - [3 -(trifluoromethyl)phenyl]propyl] - 1 -naphthalenemethanamine is commonly known as cinacalcet. (R)-Cinacalcet hydrochloride is represented by following figure.

US6011068 discloses inorganic iron receptors specifically calcium receptors. This patent generally describes cinacalcet and its pharmaceutically acceptable acid addition salt but does not provide any example for its preparation.

US6211244 discloses calcium receptor active compounds which covers cinacalcet and its pharmaceutically acceptable salt or complex.

US7250533, WO2007127445, WO2007127449, WO2008035381, WO2008058235 disclose various methods for preparation of cinacalcet or its pharmaceutically acceptable salt.

Cinacalcet and its pharmaceutically acceptable salts have been made by various processes disclosed in the prior art.

There is however, still a need to provide an economical and industrially feasible method for preparation of cinacalcet and its pharmaceutically acceptable salt. There is also a need to provide new key intermediates and isomers thereof, that are useful in the synthesis of cinacalcet or its pharmaceutically acceptable salts.

Object of the Invention

The object of the present invention is to provide a simple process for the preparation of cinacalcet or its pharmaceutically acceptable salts involving the use of key intermediates and / or isomers thereof.

It is another object of the present invention to provide processes for the preparation of key intermediates and / or isomers thereof, used in the synthesis of cinacalcet or its pharmaceutically acceptable salts.

Summary of the invention

According to one aspect of the present invention there is provided a process for preparing (cinacalcet) α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (formula I) or a pharmaceutically acceptable salt thereof which comprises: a) reacting 1-acetonaphthone with an alkyl amine or a substituted or non-substituted aralkyl amine in presence of a suitable solvent to form imine compound (formula III), which on reduction using suitable reducing agent yields N-substituted naphthyl ethyl amine (formula IV), b) optionally resolving the N-substituted naphthyl ethyl amine (formula TV) into its corresponding (R) or (S) isomer (formula IVa and IVb), c) further reacting (R, S) or (R) or (S)-N-substituted naphthyl ethyl amine (formula IV, IVa, or rVb) with trifluoromethyl aryl alkyl compound (formula V) in presence of a base and in a suitable solvent to form an intermediate corresponding to (R,S), (R) or (S)-N-substituted methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (N-substituted- cinacalcet) (formula (VI, Via or VIb), d) optionally resolving (R,S)-N-substituted cinacalcet (formula VI) into its corresponding (R) and (S) isomers (formula Via or VIb), e) converting (R,S) or (R) or (S)-N-substituted-cinacalcet (formula VI, Via or VIb) to the corresponding (R, S) or (R) or (S)-α-methyl-N-[3-[3-(trifluoromethyl)plienyl]propyl]-l- naphthalenemethanamine (cinacalcet, formula, I, Ia or Ib)) by dealkylation or debenzylation, f) optionally resolving (R,S)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine (cincacalcet, formula 1) into (R) and (S)-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (formula Ia and Ib) using a suitable resolving agent.

In another aspect of the invention there is provided intermediates for use in the synthesis of cinacalcet.

Detailed Description of the Invention

The process of the present invention can be represented as given in reaction scheme A below:

Scheme A

(Ia) (R)-Cinacalet (Ib) (S)-Cinacalcet

In one embodiment of the present invention, α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (formula I) or its pharmaceutically acceptable salt is prepared by a process which comprises the steps of :

a) converting 1-acetonaphthone (formula II) to a novel intermediate, N-substituted naphthyl ethyl amine (formula IV) via an imine compound (formula III).

(IV) N-substituted naphthyl ethyl amine

Wherein R is C₁-C₅ alkyl;or aralkyl, optionally substituted with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro, or hydroxy groups or a combination thereof. Preferably the aralkyl group is a benzyl group.

An aralkyl group, for the purposes of the present invention is defined, as any aromatic ring system bonded to an alkyl chain. The aromatic ring may comprise, for example, benzene, napthalene or anthracene. The aromatic ring may be heteroaromatic. Examples of heteroaromatic rings include pyridine and quinoline.

The conversion of 1-acetonaphthone to N-substituted naphthyl ethyl amine (formula IV), is carried out by first reacting 1-acetonaphthone with an alkyl amine or an optionally substituted aralkyl amine in presence of a suitable solvent to form imine compound (formula III) which on reduction using suitable reducing agent gives (R,S)-N-substituted naphthyl ethyl amine (formula IV).

Intermediate compound of formula (III) may be isolated or may simply be generated in situ and subjected to further reaction steps without purification.

Any suitable solvent may be used to carry out the reaction. Preferably the solvent used may be selected from the group comprising C₁-C₃ alcohols, toluene, tetrahydrofuran, diethyl ether or mixtures thereof. The reducing agent used may be selected from, but is not limited to, lithium borohydride, lithium aluminium hydride, sodium cyano borohydride, sodium triacetoxyborohydride, diborane, sodium borohydride. Preferably the reducing agent used is sodium borohydride.

Alternatively catalytic hydrogenation may be used to effect the reduction. This may be carried out using hydrogen gas in presence of palladium on carbon, platinum on carbon, platinum dioxide, Raney nickel; or a mixture thereof.

(b) Optionally at this stage the (R,S)-N-substituted naphthyl ethyl amine (formula IV) may be resolved into its corresponding (R) and (S) isomers (formula IVa or IVb) using a suitable resolving agent.

(IVa) (IVb) (R)-N-substituted naphthyl ethyl amine (S)-N-substituted naphthyl ethyl amine

The resolving agent used for resolution of racemic amine (formula IV) may be selected from camphor sulphonic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-p-anisoyl tartaric acid, di-p-pivaloyl tartaric acid, benzenesulfonyl aspartic acid or their optically active antipodes.

The resolution process employed may be diastereomeric resolution, kinetic resolution, chiral chromatography, enzymatic resolution, extraction with chiral solvents or simulated moving bed technology (SMBT).

(c) The (R,S), (R) or (S)-N-substituted naphthyl ethyl amine (formula IV, IVa, or IVb) is then reacted with trifluoromethyl aryl alkyl compound (formula V) in presence of a base and in a suitable solvent to generate intermediate, (R₅S) or (R) or (S)-N-substituted-cinacalcet (formula VI, Via or VIb).

N-substituted-Methyl-N-[3-[3-(trifluoromethyl)phenyl] propyl] - 1 -naphthalenemethanamine

Wherein R is C₁-C₅ alkyl; or aralkyl, optionally substituted with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro, or hydroxy groups or a combination thereof. Preferably the aralkyl group is a benzyl group.

The leaving group "L" as shown in trifluoromethyl aryl alkyl compound (formula V) represents any suitable leaving group. Preferably the "L" group represents an -OMs (mesylate), -OTs (Tosylate), -OTf (triflate), acetate, trifluoroacetate, -Br, Cl, or Iodine group. More preferably the "L" group represents a "-OMs" (mesylate) group.

The base used in this reaction step may be an inorganic or an organic base.

The inorganic base may be selected from group comprising of alkali metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide; and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or mixtures thereof.

The organic base may be selected from the group comprising aliphatic amines or aromatic amines. Preferably the organic base can be selected from the group comprising, but not limited to, triethyl amine, di-isopropyl amine, di-isopropylethyl amine, pyridine, picoline, diethyl amine and piperidine or mixtures thereof.

A suitable solvent may be a neutral organic solvent which is selected from group of solvents such as, ketone containing solvents, nitrile containing solvents and polar solvents.

Preferably the solvent may be selected from the group comprising acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, water, dimethyl formamide, tetrahydrofuran and dimethyl sulfoxide or mixtures thereof.

The reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent.

(d) Optionally, at this stage of the process the (R,S)-N-substituted-cinacalcet (formula VI) may be resolved into its isomers of (R) or (S)-N-substituted cinacalcet (formula Via and VIb)

(R)-N-substituted alpha-Methyl-N-[3-[3-(trifluoromethyl) (S)-N-substituted alpha-methyl-N-[3-[3-(trifluoromethyl) phenyl]propyl] - 1 -naphthalenemethanamine phenyl]propyl]-l-naphthalenemethanamine

The resolving agent used for resolution of N-substituted cinacalcet (formula VI) may be selected from camphor sulphonic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-p-anisoyl tartaric acid, di-p-pivaloyl tartaric acid, benzenesulfonyl aspartic acid or their optically active antipodes. Resolution processes employed may be diastereomeric resolution, kinetic resolution, chiral chromatography, enzymatic resolution, extraction with chiral solvents or simulated moving bed technology (SMBT).

e) The (R₅S), (R) or (S)-N-substituted-cinacalcet (formula VI, Via or VIb) is further converted to the corresponding (R₅S), (R) or (S) cinacalcet (formula I₅ Ia₅ or Ib) by dealkylation or debenzylation.

Dealkylation or debenzylation may be carried out by using suitable reagents such as alkyl, aryl or substituted alkyl or substituted aryl chloroformates; K[Fe(CN)₆]; acetone- azodicarboxylate followed by hydrolysis; triphosgene; and cyanogen bromide, in suitable solvents.

Preferred chloroformates include, but are not limited to, ethyl chloroformate, 1-chloroethyl chloroformate, vinyl chloroformate, phenyl chloroformate, 2,2,2-trichloroethyl chloroformate, 4-chlorophenyl chlorothionoformate and 2,4,6-tribromophenyl chlorothionoformate. The most preferable chloroformates are 1-chloroethyl chloroformate or thiochloroformate.

Dealkylation using chloroformates may require the presence of a base. The base may be an organic base. The organic base may be selected from the groups comprising aliphatic amines or aromatic amines. Preferably the organic base may be selected from the group comprising, triethyl amine, di-isopropyl amine, di-isopropylethylamine, pyridine, picoline, diethyl amine and piperidine and mixtures thereof.

Any suitable solvent may be used for the reaction. Preferably the solvent used for the dealkylation or debenzylation step may be selected from the group comprising methylene dichloride, ethylene dichloride, toluene, benzene, xylene, ethyl acetate or mixtures thereof.

Debenzylation may also be carried out by hydrogenation using catalytic hydrogenation or hydrogen transfer agent. Catalytic hydrogenation may be carried out using noble metal catalysts such as palladium on carbon, platinum on carbon, platinum dioxide, palladium hydroxide, palladium on alumina, Raney nickel, rhodium on alumina, rhodium on carbon and ruthenium on carbon.

Transfer hydrogenation may be carried out using hydrogen donor reagent such as alcohols like isopropanol; amines such as ethyl amine, propyl amine, isopropyl amine, dibutyl amine, dihexyl amine, benzylamine, dibenzyl amine, piperidine; cyclohexadiene, tetraline, dihydrofuran, quinoline, 1,4-butanediol, hydrazine hydrate and hydrogen source can be selected from formic acid, sodium formate, ammonium formate.

Preferably, dealkylation is carried out using 1-chloroethylchloroformate in the presence of a base such as Hύnig's base (i.e. N,N-diisopropylethylamine) to form a carbamate intermediate, which is hydrolysed by refluxing in an alcohol for example methanol, ethanol, isopropyl alcohol or butanol to give (R,S), (R) or (S) cinacalcet (formula I, Ia, or Ib).

f) Optionally resolving (R,S)-cinacalcet (formula I) into (R) -cinacalcet (formula Ia) or (S)- cinacalcet (formula Ib) using suitable resolving agent.

(R)-cinacalcet (S)-cinacalcet

A suitable resolving agent for resolution of cinacalcet (formula (I) may be selected from camphor sulphonic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-p-anisoyl tartaric acid, di-p-pivaloyl tartaric acid, benzenesulfonyl aspartic acid or their optically active antipodes. The resolution processes employed may be a diastereomeric resolution, kinetic resolution, chiral chromatography, enzymatic resolution, extraction with chiral solvents, or simulated moving bed technology (SMBT).

Overall the process of the present invention can be represented as given in reaction scheme A below:

Scheme A

(Ia) (R)-Cinacalet (Ib) (S)-Cinacalcet (R)-cinacalcet can also be prepared from the corresponding chiral intermediates using the process of the present invention. This foπns another aspect of the present invention.

In yet another embodiment of the present invention, (R,S)-N-substituted naphthyl ethyl amine (formula IV) is resolved into its corresponding isomers (formula IVa or IVb) using suitable resolving agent.

Resolved (R) or (S)-isomers (formula IVa or IVb) is reacted with trifluoromethyl aryl alkyl compound (formula V) in presence of a base and in a suitable solvent to get corresponding (R) or (S)-N-substituted-(α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine) cinacalcet (formula Via or VIb).

Suitable solvent & base used for the reaction are same as those described in step c).

(R)-N-substituted alpha-Methyl-N-[3-[3-(trifluoromethyl) (S)-N-substituted alpha-methyl-N-[3-[3-(trifluoromethyl) phenyl]propyl]-l-naphthalenemethanamine phenyljpropyl]- 1 -naphthalenemethanamine

(R) or (S)-N-substituted-(α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l - naphthalenemethanamine)cinacalcet (formula Via or VIb) is then further dealkylated or debenzylated to get (R) or (S)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine .

Dealkylation or debenzylation is carried in a similar manner as described in step e).

In another embodiment of the present invention, (R,S)-N-substituted-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine cinacalcet (formula VI) is resolved into its isomers (formula Via or VIb). (R) or (S)-N-substituted-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine cinacalcet (formula Via or VIb) is then further dealkylated or debenzylated to get (R) or (S)-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine.

Resolving agent used for resolution of racemic N-substituted naphthyl ethyl amine (formula (IV) or racemic N-substituted cinacalcet (formula VI) or racemic cinacalcet is selected from camphor sulphonic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-p-anisoyl tartaric acid, di-p-pivaloyl tartaric acid, benzenesulfonyl aspartic acid or their optically active antipodes-

Resolution processes employed can be diastereomeric resolution, kinetic resolution, chiral chromatography, enzymatic resolution, extraction with chiral solvents, simulated moving bed technology (SMBT).

Resolved (R) or (S) α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine obtained is further converted into its pharmaceutically acceptable salt.

In yet another embodiment of the invention, the diastereomeric salt of (R) or (S)-N- substituted naphthyl ethyl amine (formula IV) is condensed with trifluoromethyl aryl alkyl compound (formula V) in an aqueous medium to get of (R) or (S)-N-substituted-α-methyl- N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine cinacalcet (formula Via or VIb) respectively. (R) or (S)-N-substituted-(α-methyl-N-[3-[3-

(1xifluoromethyl)phenyl]propyl]-l-naphthalenemethanarnine)cmacalcet (formula Via or VIb) on further dealkylation or debenzylation gives corresponding isomer of α-methyl-N-[3-[3- (1τifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine.

Typically using the process of the present invention, (R)-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine is prepared by reacting 1- acetonaphthone with methanolic methyl amine at reflux temperature to give intermediate imine. The imine so obtained is reduced using sodium borohydride in presence of methanol to give N-methylnaphthyl ethyl amine. N-methylnaphthyl ethyl amine is reacted with 3-[3- (trifluoromethyl)phenyl]propyl bromide in presence of potassium carbonate in acetonitrile at reflux temperature to give N-methyl-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine. N-methyl-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine which is then demethylated by treating with 1-chloroethyl chloroformate in toluene and hydrolysis of the resulting carbamate by methanol which yields racemic α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine.

Racemic α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l -naphthalenemethanamine is then resolved to obtain desired (R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine.

The present invention will now be further illustrated by the following examples, which do not limit the scope of the invention in any way.

Examples

Example 1 - Preparation Compound III

1-acetonapthone (250 g, 1.47 mols) was charged to a polyclave along with 2.5 litres of methanolic methyl amine (20%) at 25-30°C. The temperature was raised to 65°C and reaction mixture was maintained at this temperature for 8 hours. The reaction mass was then cooled to 25-30°C and the solvent was distilled off at 50°C under vacuum to yield an oil. Yield - 245.8 g (91% of theory) In a similar manner compound III, [N-(l-(naphthalen-l-yl)ethylidene)(4- nitrophenyl)methanamine] was prepared from 4-nitrobenzyl amine.

Example 2 - Preparation of racemic compound IV HCl salt.

1.7 litres of methanol and compound III (245 g, 1.34 mols) obtained in example 1 were charged into a 5L reaction flask and cooled to between 0 to 5°C. Sodium borohydride (81.39 g, 2.14 mols) was then added portion wise over 1 hour and the reaction mixture was then maintained for a further 2 hours at 0-5°C. The temperature was then raised to 25-3O⁰C and maintained for a further 2 hours. The solvent was then distilled off at 50°C under vacuum to provide an oil. The resulting oil was mixed with 500 niL water and 500 mL toluene and stirred for 30 minutes at 25-3O⁰C. The layers were separated and the toluene layer was washed twice with 500 mL water followed by 500 mL saturated sodium chloride solution and dried over sodium sulphate. The sulphate was then removed by filtration and the solution, cooled to between 0°C to 5⁰C. 400 mL of isopropanolic HCl was then added dropwise over 1 hour. The mixture was stirred for a further 2 hours. The solid obtained was filtered, washed twice with 250 mL of chilled toluene and dried in vacuum oven at 55°C - 60⁰C for 10 hours. Yield - 245 g (83% of theory)

In a similar manner racemic compound IV HCl salt [l-(naphthalen-l-yl)-N-(4- nitrobenzyl)ethanamine HCl salt] was prepared from corresponding compound III, [N-(I- (naphthalen- 1 -yl)ethylidene)(4-nitrophenyl)methanamine] .

Example 3 - Preparation of (ID-compound FV tartrate

Racemic compound IV (170 g, 0.92 mol) was added to a solution of 170 mL of ethanol and 1.5 litres of water in a reaction flask at 25-3O⁰C and stirred for 15 minutes. L-tartaric acid (137.9 g, 0.92 mol) was then added in one portion, (an exotherm was observed). A clear solution was obtained and it was stirred for 15 minutes at 25-3O⁰C. The solid was precipitated in a reaction mass which was heated to 75 to 80⁰C and maintained for 3 hours and then cooled gradually to 25-30⁰C. The reaction mass was stirred for 2 hours at 25-30⁰C, filtered solid and washed with 200 inL of ethanol. This R isomer was purified using ethanol & water (1:9) mixture to get the desired chiral purity. Yield - 135 g (88% of theory).

Similarly another (R)-compound IV tartrate [(R)-l-(naphthalen-l-yl)-N-(4- nitrobenzyl)ethanamine DPTTA salt] was prepared by resolution of compound IV [1- (naphthalen-l-yl)-N-(4-nitrobenzyl)ethanamine] using (-)-di-para-D-toluoyl tartaric acid.

In a similar manner, (S)-compound IV tartrate [(S)-N-methyl-l-(naphthalen-l-yl)ethanamine tartrate] was also prepared using D-tartaric acid & (S)-compound IV DPTTA [(S)-I- (naphthalen-l-yl)-N-(4-nitrobenzyl)ethanamine DPTTA salt] was prepared by using (+)-di- para-L-toluoyl tartaric acid.

Example 4 — Preparation of racemic compound VI

250 mL of purified water was charged to a clean reaction flask followed by potassium carbonate (62.4 g, 0.45 mol) and 3-[3-(trifluoromethyl)phenyl]propyl methanesulphonate (96.4 g, 0.34 mol) at 25-30⁰C. The reaction mixture was heated to 60⁰C - 65⁰C and compound IV HCl salt (50 g, 0.23 mol) was added in one lot, stirred at 60-65⁰C for 20 hours. After cooling to 25-3O⁰C, the reaction mass was extracted twice with 250 mL of ethyl acetate and organic layer was washed twice with 150 mL of purified water and with 150 mL of saturated brine solution. The organic layer was dried over sodium sulphate and the solvent was distilled off at 5O⁰C under high vacuum till dryness to obtain an oil. Yield - 7Og (83% of theory)

In a similar manner racemic compound VI [N-(l-(naphthalen-l-yl)ethyl)-N-(4- nitrobenzyl)-3-(3-(trifluoromethyl)phenyl)propan-l-amine] was prepared from compound IV [l~(naphthalen-l-yl)-N-(4-nitrobenzyl)ethanamine].

Example 5 - Preparation of (R) compound VI tartrate

The compound VI obtained from example 4 (70 g, 0.18 mol) was dissolved in 250 mL of ethyl acetate in a clean flask and (-)-di-para-D-toluoyl tartaric acid (70 g, 0.18 mol) was added lot wise (Exotherm was observed). The reaction mass was stirred for 15 minutes at 25- 3O⁰C and further stirred at 65°C temperature for 30 minutes. The reaction mass was cooled to 0-5⁰C, stirred for 2 hours and the solid obtained was filtered and washed twice with 50 mL of chilled ethyl acetate and suck dried. The solid was dried in vacuum oven at 55-60⁰C for 10 hours. Yield- 53 g (74.3% of theory)

Similarly (R) compound VI DPTTA [(R)-N-(l-(naphthalen-l-yl)ethyl)-N-(4-nitrobenzyl)-3- (3-(trifluoromethyl)phenyl)propan-l-amine DPTTA salt] was prepared by resolution of compound VI [l-(naphthalen-l-yl)-N-(4-nitrobenzyl)ethanamine DPTTA] using (-)-di-para- D-toluoyl tartaric acid.

hi a similar manner, (S) compound VI tartrate [(S)-N-methyl-l-(naphthalen-l-yl)ethanamine tartrate] was also prepared using D-tartaric acid & (S) compound VI DPTTA [(S)-I- (naphthalen-l-yl)-N-(4-nitrobenzyl)ethanamine DPTTA salt] was prepared by using (+)-di- para-L-toluoyl tartaric acid.

Example 6 - Preparation of racemic cinacalcet.

Dried racemic compound VI (5 g, 0.013 mol) was charged into a clean flask followed by toluene 50 mL at 25-30°C and cooled to 10-15⁰C. 1-Chloroethyl chloroformate (2.78 mL, 0.019 mol) was added slowly to reaction mass between 10-20⁰C within 60 minutes (Exotherm observed) and stirred for 30 minutes. Diisopropylethyl amine (1.54 mL, 0.0065 mol) was charged to the reaction mass at 10-20⁰C in one lot and stirred for 30 minutes. Reaction mass was heated to 60-65 °C for 2-3 hours and 10 mL methanol was added slowly within 1 hour. The reaction mass was further heated for 2-4 hours at 60-65⁰C. Reaction mass was concentrated at 60-65⁰C to remove methanol, cooled to 25-30°C and 15 mL of water was added and stirred for 30 minutes. The layers were separated and aqueous layer was re- extracted twice with 10 mL toluene. Toluene layer was separated and discarded. pH of an aqueous layer was adjusted to 9-10 using 25% ammonia solution, 20 ml toluene was added and stirred for 30 minutes. The layers were separated and the aqueous layer re-extracted twice with 20 mL toluene. Toluene layer was washed with 20 mL water and washed twice with 20 mL saturated brine solution. Toluene solution was dried over sodium sulphate, filtered through hyflow and was charcoalised with 0.5 g charcoal and filtered through hyflow. Finally the toluene was evaporated at 50-60°C under vacuum to get oil. Yield- 3.2 g (66.6% of theory)

Example 7 - Preparation of racemic cinacalcet.

Compound VI (10 g, 0.02 mol) along with 100 mL of methanol were charged to hydrogenating vessel followed by addition of 2.0 g of 5% Pd-C. The reaction mass was hydrogenated at atmospheric pressure at 25-30°C for 10-12 hours and filtered through hyflo, cake was washed with 100 mL methanol. Methanol was evaporated at 50°C under high vacuum to get oil.

Yield- 5 g (69% of theory)

Example 8 - Preparation of (RVcinacalcet.

Dried oil of (R)-compound VI (25 g, 0.05 mol) was charged in a clean reactor at 25-3O⁰C followed by 250 mL of toluene. The reaction mixture was cooled to 10-15°C and 1- Chloroethyl chloroformate (10.80 mL, 0.075 mol) was added slowly to reaction mass between 10-20⁰C within 60 minutes (Exotherm observed). The reaction mass was stirred for 30 minutes at 10-20⁰C. Diisopropylethyl amine (3.2 g, 0.025 mol) was added to the reaction mass in one lot and stirred for 30 minutes. The reaction mass was heated to 60-65⁰C for 2-3 hours and 10 mL of methanol was added slowly to it within 1 hour. The reaction mass was heated further for 2-4 hours at 60-65⁰C and concentrated to remove methanol. The residue was cooled to 25-30⁰C and 75 mL of water was added to it and stirred for 30 minutes. The toluene layer was separated and aqueous layer was again washed twice with 50 ml toluene. Toluene layer separated and discarded. Aqueous layer was taken in a clean reactor and 50 mL ammonia solution (pH 9-10) was added to it followed by 100 mL toluene and stirred for 30 minutes. Toluene layer was separated. Aqueous layer was again extracted twice with 100 mL toluene. Toluene layer was washed with 100 mL water and twice with 100 mL saturated brine solution. Toluene layer was dried over sodium sulphate, filtered through hyflow and charcoalised with 0.5 g charcoal, again filtered through hyflow and finally evaporated at 50- 60⁰C under vacuum to get oil. Yield- 10 g (55% of theory)

Example 9 - Resolution of racemic cinacalcet.

Racemic cinacalcet (32 g, 0.0896 mol) was transferred along with 20 ml of ethyl acetate and (-)-di-para-D-toluoyl tartaric acid (36 g, 0.0896 mol) was added lot wise (Exotherm was observed) and stirred for 15 minutes at 25-30°C and further stirred at 65°C for 30 minutes. The reaction mass was cooled to 0-5⁰C, stirred for 2 hours and the solid obtained was filtered and washed twice with 50 mL of chilled ethyl acetate and suck dried. The obtained DPTTA salt of cinacalet was dried in vacuum oven at 55-60°C for 10 hours. The so obtained salt was further recrystallised from ethyl acetate. Yield - 25 g (78% of theory)

Preparation of Cinacalcet HCl salt. Preparation of free base of Cinacalcet

Cinacalcet DPTTA salt (25 g) obtained in above step was suspended in 50 mL of methylene dichloride (MDC) and 50 mL of water. The pH of the solution was adjusted to 9 to 10 using 10% sodium hydroxide solution. The reaction mass was stirred for 30 minutes and layers were separated. The aqueous layer was re-extracted twice with 20 mL of MDC. The combined organic layer was dried over sodium sulphate, filtered through celite and evaporated completely to obtain the oil of (R)-cinacalcet base. Yield- 11.5 g (96% of theory)

(R)-Cinacalcet base as obtained above was dissolved in ethyl acetate (50 mL) & transferred into the reaction flask. The pH was adjusted to between 2-3 using 20% isopropanolic HCl by drop wise addition at 25-3O⁰C and stirred for 30 minutes and further stirred at reflux temperature for 30 minutes to ensure the complete formation of HCl salt. The product obtained was cooled to 0- 5⁰C within 2 hours and stirred for 1 hour. The solid obtained was filtered and washed twice with 20 mL of chilled ethyl acetate, suck dried and finally dried in vacuum oven at 55-60°C for 10 hours to get (R)-cinacalcet HCl. This HCl salt was recrystallised from ethyl acetate. Yield - 10.2 g (80% of theory) Cinacalcet was also prepared from following different compounds instead of 4-nitrobenzyl amine via corresponding intermediate compound (IV) and compound (VI)

Claims

Claims:

1. A process for preparing (cinacalcet) α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-1-naphthalenemethanamine (formula I)

or a pharmaceutically acceptable salt thereof which comprises: a) reacting 1-acetonaphthone with an alkyl amine or a substituted or non-substituted aralkyl amine in presence of a suitable solvent to form imine compound (formula III), which on reduction using suitable reducing agent yields N-substituted naphthyl ethyl amine (formula IV), b) optionally resolving the N-substituted naphthyl ethyl amine (formula (IV) into its corresponding (R) or (S) isomer (formula IVa and IVb), c) further reacting (R₁S) or (R) or (S)-N-substituted naphthyl ethyl amine (formula IV, IVa, or IVb) with trifluoromethyl aryl alkyl compound (formula V) in presence of a base and in a suitable solvent to form an intermediate corresponding to (R₁S), (R) or (S)-N-substituted-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1- naphthalenemethanamine (N-substituted-cinacalcet) (formula Vl, Via or VIb), d) optionally resolving (R.S)-N-substituted cinacalcet (formula VI) into its corresponding (R) and (S) isomers (formula Via or VIb), e) converting (R₁S) or (R) or (S)-N-substituted-cinacalcet (formula Vl, Via or VIb) to the corresponding (R₁S) or (R) or (S)-α-Methyl-N-[3-[3-

(trifluoromethyl)phenyl]propyl]-1-naphthalenemethanamine (cinacalcet) (formula, I, Ia or Ib)) by dealkylation or debenzylation, f) optionally resolving (R,S)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyI]-1- naphthalenemethanamine (cincacalcet, formula I) into (R) and (S)-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-1-naphthalenemethanamine (formula Ia and Ib) using a suitable resolving agent.

2. A process according to claim 1 , wherein the reduction in step a) is carried out by catalytic hydrogenation; or by using a reducing agent selected from group comprising lithium borohydride, lithium aluminium hydride, sodium cyano borohydride, sodium triacetoxyborohydride, diborane, sodium borohydride.

3. A process according to claim 2 wherein the catalytic hydrogenation is carried out using hydrogen gas in presence of either palladium on carbon, platinum on carbon, platinum dioxide, Raney nickel, or a combination thereof.

.

4 A process according to any of the preceding claims wherein the suitable solvent for step a) is selected from group comprising of C₁-C₃ alcohols, toluene, tetrahydrofuran, diethyl ether or mixtures thereof.

5. A process according to any of the preceding claims wherein the base used in step c) is selected from an inorganic or an organic base.

6. A process according to claim 5 wherein the inorganic base is selected from the group comprising alkali metal carbonates, preferably cesium carbonate, sodium carbonate, potassium carbonate; alkali metal alkoxides, preferably sodium methoxide, sodium ethoxide, potassium tertiary butoxide; and alkali metal hydroxides, preferably sodium hydroxide, potassium hydroxide; or mixtures thereof.

7. A process according to claim 5 wherein the organic base is selected from the group comprising aliphatic or aromatic amines, and wherein preferably the aliphatic amines or aromatic amines are selected from the group comprising triethylamine, di- isopropylamine, diisopropylethylamine, pyridine, picoline, diethyl amine, piperidine or mixtures thereof.

8. A process according to any of the preceding claims wherein step c) is carried out in presence of suitable solvent selected from group of ketone containing solvents, preferably acetone, methyl isobutyl ketone, methyl ethyl ketone; nitrite containing solvents, preferably aetonitrile; and polar solvents, preferably water, dimethyl formamide, tetrahydrofuran, or dimethyl sulfoxide; or mixtures thereof.

9. A process according to any of the preceding claims, wherein dealkylation or debenzylation in step e) is carried out using suitable agents such as alkyl, aryl or substituted alkyl or substituted aryl chloroformates and mixtures thereof; wherein in preferably the chloroformates are selected from the group comprising ethyl chloroformate, 1-chloroethyl chloroformate, vinyl chloroformate, phenyl chloroformate, 2,2,2-trichloroethyl chloroformate, 4-chlorophenyl chlorothionoformate and 2,4,6-tribromophenyl chlorothionoformate.

10. A process according to any one of claims 1 to 9, wherein the dealkylation or debenzylation in step e) is carried out using a suitable agent such as K[Fe(CN)6], or acetone-azodicarboxylate followed by hydrolysis, or by using triphosgene, or by using cyanogen bromide.

11. A process according to any preceding claim wherein the solvent used in step e) is selected from the group comprising methylene dichloride, ethylene dichloride, toluene, benzene, xylene, ethyl acetate or mixtures thereof.

12. A process according to any one of claims 1-8, wherein debenzylation is carried out by hydrogenation using catalytic hydrogenation or a hydrogen transfer agent.

13. A process according to claim 12 wherein the catalytic hydrogenation is carried out using a noble metal catalyst such as palladium on carbon, platinum on carbon, platinum dioxide, palladium hydroxide, palladium on alumina, Raney nickel, rhodium on alumina, rhodium on carbon, ruthenium on carbon or a mixture thereof.

14. A process according to claim 12 wherein the transfer hydrogenation is carried out using a hydrogen donor reagent such as alcohol like isopropanol; amines such as ethyl amine, propyl amine, isopropyl amine, dibutyl amine, dihexyl amine, benzylamine, dibenzyl amine, piperidine; cyclohexadiene, tetraline, dihydrofuran, quinoline, 1 ,4-butanediol, hydrazine hydrate and hydrogen source can be selected from formic acid, sodium formate, ammonium formate.

15. A process according to any preceding claim wherein the resolving agent used for resolution of racemic compound of formula (IV), (Vl) or (I) is selected from the group comprising camphor sulphonic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, di-p-anisoyl tartaric acid, di-p-pivaloyl tartaric acid, benzenesulfonyl aspartic acid or their optically active antipodes.

16. A process according to any one of claims 1 - 15 wherein the resolution processes employed for resolution of racemic compound of formula (IV), (Vl) or (I) comprises diastereomeric resolution, kinetic resolution, chiral chromatography, enzymatic resolution, extraction with chiral solvents, simulated moving bed technology (SMBT).

17. A compound of formula IV, N-substituted napthyl ethyl amine;

(IV)

N-substituted naphthyl ethyl amine wherein R is Ci-C₅ alkyl; or aralkyl, optionally substituted on the aryl ring with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro or hydroxy groups or a combination thereof, and wherein preferably the aralkyl is a benzyl group.

18. A compound of formula IVa, (R)-N-substituted napthyl ethyl amine,

(IVa) (R)-N-substituted naphthyl ethyl amine

wherein R is C1.C5 alkyl; or aralkyl, optionally substituted on the aryl ring with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro or hydroxy groups or a combination thereof; and wherein preferably the aralkyl is a benzyl group.

19. A compound of formula IVb, (S)-N-substituted naphthyl ethyl amine;

(IVb) (S)-N-substituted naphthyl ethyl amine

wherein R is Ci-Ce alkyl; or aralkyl, optionally substituted on the aryl ring with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro or hydroxy groups, or a combination thereof; and wherein preferably the aralkyl is a benzyl group.

20. A compound of formula Vl, N-substituted-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-1-naphthalenemethanamine,

N-substituted-Methyl-N- [3 - [3 -(trifluoromethyl)phenyl] propyl] - 1 -naphthalenemethanamine wherein R is CrC₅ alkyl; or aralkyl, optionally substituted on the aryl ring with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro or hydroxy groups or a combination thereof, and wherein preferably the aralkyl is a benzyl group.

21. A compound of formula (Via), (R)-N-substituted-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-1 -naphthalenemethanamine,

(R)-N-substituted alpha-Methyl-N-[3-[3-(trifluoromethyl) phenyl]propyl] - 1 -naphthalenemethanamine

wherein R is C₁-C₅ alkyl; or aralkyl, optionally substituted on the aryl ring with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro or hydroxy groups or a combination thereof, and wherein preferably the aralkyl is a benzyl group.

22. A compound of formula (VIb), (S)-N-substituted-α-methyl~N-[3-[3- (trifluoromethyl)phenyl]propyl]-1-naphthalenemethanamine,

(S)-N-substituted alpha-methyl-N- [3- [3 -(trifluoromethyl) phenyl]propyl]-l-naphthalenemethanamine

wherein R is Ci-C₅ alkyl; or aralkyl, optionally substituted on the aryl ring with one or more alkyl, alkoxy, haloalkyl, halo, cyano, nitro or hydroxy groups or a combination thereof, and wherein in preferably the aralkyl is a benzyl group.

23. A process according to any one of claims 1 to 16, wherein the (R,S), (R) or (S)- α-methyl-N-[3-[3-(trifluoromethyI)phenyI]propyl]-1-naphthalenemethanamine obtained is further converted into a pharmaceutically acceptable salt.