, Description:Field of the Invention
The present invention generally relates to the field of synthetic chemistry, and more particularly, to an improved process for the preparation of cinacalcet hydrochloride and its intermediate sodium {1-hydroxy-3-(3-trifluoromethyl phenyl) propyl} sulfonate (Bisulphite adduct).

Background of the Invention
Cinacalcet hydrochloride (I), chemically N-[1-(R)-(-)-(1-naphthyl) ethyl]-3-[3-trifluoro methyl) phenyl]-1-aminopropane hydrochloride, and other calcium receptor-active molecules having the general structure of cinacalcet, are disclosed in U.S. Pat. Nos. 6,011,068 and 6,211,244. It is a calcimimetic agent that increases the sensitivity of para thyroid calcium-sensing receptors to serum calcium. It is commercially available
under the brand name Sensipar® and has been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

Formula (I)

Cinacalcet and its enantiomers may be produced by various methods reported in U.S. Pat. No. 6,211,244 and DRUGS OF THE FUTURE (2002) 27(9): 831-836.

In accordance to the process disclosed in U.S. Pat. No. 6,211, 244 and DRUGS OF THE FUTURE (2002) 27 (9):831-836, cinacalcet may be produced by reacting (R)-(1-naphthyl) ethylamine (II) with 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) in the presence of titaninum tetraisopropoxide to produce the imine that corresponds to cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride.

These processes, however, require the use of reagents such as titanium tetraisopropoxide which is highly hygroscopic and toxic, and ethanolic or methanolic sodium cyanoborohydride, which is highly toxic and flammable, making the processes difficult to manage on industrial scale.

An alternative process is described in WO2006/125026, involving conversion of hydroxyl group of 3-(3-trifluoromethyl phenyl) propanol to a good leaving group and then combining with 1- naphthyl ethyl amine in presence of base.

WO 2007/127445 discloses another process involving condensation of reactive derivative of 3-trifluoromethyl phenyl propanoic acid with 1-naphthyl ethyl amine in presence of base of obtain corresponding propanamide intermediate, which is reduced to obtain cinacalcet.

WO 2007/127449 discloses another process of heating the mixture of 3-bromo-trifluoro toluene and ally amine compound to obtain unsaturated Cinacalcet base which is reduced to obtain cinacalcet.

Tetrahedron letters (2004) 45: 8355-8358, discloses the preparation of the starting material 3-[3-(trifluoromethyl)phenyl]propionaldehyde by reduction of 3-(trifluoro methyl) cinnamic acid to the corresponding alcohol followed by oxidation to give the desired aldehyde, as depicted in the following Scheme I.

(Scheme I)

WO 2008/035212 describes the process for the preparation of cinacalcet intermediate bisulphite adduct (IIIa) by oxidation of 3-(3-trifluromethylphenyl)propan-1-ol (IX) using oxidizing agent like sodium hypochlorite in the presence of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO) as a catalyst in Toluene and potassium bromide (KBr) in water. Organic layer is stirred with a solution of Sodium bisulphite in water at 100-110°C to get Bisulphite adduct (IIIa), as depicted in the following Scheme 2, which is isolated by filtration.

(Scheme 2)

Indian Pat. Appl. No. 1367/MUM/2009 discloses the process for preparation of cinacalcet by reacting 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) in heptane with aqueous Sodium bisulphite to obtain bisulphite adduct (IIIa), which is treated with sodium carbonate to obtain 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III), which is further treated with R-(+)-(1- naphthyl) ethylamine (II) and sodium borohydride to obtain cinacalcet, as depicted in Scheme 3.

(Scheme 3)

Another process is describes in Indian Pat. Appl. No. 2268/DEL/2008 for preparing cinacalcet by treating 3-trifluoromethylaniline (V) with hydrochloric acid and sodium nitrite (NaNO2), followed by reaction with acrolein (Vb) in the presence of metal catalyst to give 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III), which is treated with sodium bisulphite to get bisulphite adduct (IIIa), which is further treated with R-(+)-(1-naphthyl) ethylamine (II) or its salt and sodium borohydride under alkaline condition to obtain Cinacalcet, as depicted in Scheme 4.

(Scheme 4)

Indian Pat. Appl. No. 2747/CHE/2014 discloses a process for preparation of cinacalcet starting from 3-(3-trifluoromethyl) phenyl propanol (IX).

Indian Pat. Appl. No. 882/CHE/2012 discloses processes for the preparation of 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III). In one of the processes, 3-(3-trifuoro methyl phenyl) propanol of formula (IX) is oxidized with a hypochlorite, in the presence of 2, 2, 6, 6-tetramethyl 1-piperidinyloxy free radical (TEMPO) and aqueous hydrogen carbonate to provide 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III).
In another process, 3-trifluromethyl aniline of formula (V) is treated with sodium nitrite and palladium compound under acidic conditions in a solvent followed by reaction with allyl alcohol (VI) to provide 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III), as depicted in Scheme 5.

(Scheme 5)

The purity of 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) mentioned is 70.16% by HPLC.

Indian Pat. Appl. No. 882/CHE/2012 further discloses the process for preparation of bisulphite adduct (IIIa) by adding 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) in toluene to a mixture of sodium bisulphite in water followed by heating to 102°C and stirring at that temperature for 1.5 hr and isolating the bisulphite adduct (IIIa) by filtration and drying. The purity of bisulphite adduct (IIIa) mentioned is 93.38% by HPLC.

The Bisulphite adduct is reacted with R-(+)-(1- naphthyl) ethylamine (NEA) (II), toluene and sodium triacetotoxy borohydride to obtain cinacalcet which is converted in to hydrochloride salt by treatment with hydrochloric acid in a large volume of mixture of solvents consisting of ethyl acetate, diisopropyl ether (DIPE) and water.

However, use of low purity bisulphite adduct (93.38% by HPLC) in the synthesis of cinacalcet hydrochloride necessitates use of large volume of mixture of solvents for purging the impurities that get carried over from bisulphite adduct to cinacalcet. Further, diisopropyl ether is very hazardous due to presence of peroxide impurities and use of water in the mixture of solvents, makes it difficult to recover and recycle individual solvent, hence making process uneconomical and environmentally unfriendly.
Also, the use of high temperature in the formation of bisulphite adduct (IIIa) makes the process unsafe whereas the use of mixture of toluene and water in the process, results in slow rate of filtration during isolation, which reduces productivity.

Hence, there is a need to provide an alternate yet improved process for preparing cinacalcet using highly pure bisulphite adduct intermediate, which is industrially safe and scalable.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of cinacalcet hydrochloride of formula (I) using sodium {1-hydroxy- 3-(3-trifluoro methyl phenyl) propyl} sulfonate (bisulphite adduct) (IIIa) of more than 99.5% purity.

In a preferred aspect, the present invention provides a process for preparing sodium {1-hydroxy- 3-(3-trifluoro methyl phenyl) propyl} sulfonate of more than 99.5% purity, which comprises the step of:
(a) adding ally alcohol (VI) to a reaction mixture of 3-trifluromethyl aniline (V), source of nitrous acid and palladium catalyst

in a mixture of acetonitrile and water at a temperature between 0°C to 35°C to obtain 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III);

(b) extracting 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) obtained in step (a) in a water immiscible solvent and reacting with aqueous sodium bisulphite;

(c) adding metal chloride to an aqueous layer separated from step (b) and isolating the precipitated bisulphite adduct (IIIa) by filtration.

In another aspect, the present invention provides an improved process for preparing cinacalcet hydrochloride (I), which comprises the step of:
(a) reacting bisulphite adduct (IIIa) with aqueous alkali in a water immiscible solvent;
(b) mixing a solvent selected from a group consisting of methyl alcohol, ethyl alcohol, propyl alcohol and isopropyl alcohol to an organic layer separated from step (a) and reacting with 1.0 to 1.3 mole equivalent of R-(+)-1-(1-naphthyl) ethyl amine (II)

in the presence of hydride transfer agent selected from a group consisting of sodium triacetoxy borohydride, sodium borohydride, lithium borohydride and potassium borohydride to obtain cinacalcet (Ia);

(c) reacting cinacalcet obtained in step (b) with hydrogen chloride in ethyl acetate to obtain cinacalcet hydrochloride;
(d) repulping cinacalcet hydrochloride obtained in step (c) in hot water; and
(e) filtering cinacalcet hydrochloride obtained in step (d) to isolate solid cinacalcet hydrochloride.

Detailed Description of the Invention
3-[3-(trifluoromethyl) phenyl] propionaldehyde or FMPP (III) is one of the key intermediates used in the preparation of cinacalcet hydrochloride (I). In various prior art, synthesis of 3-[3-(trifluoromethyl) phenyl] propionaldehyde involves mainly either of the two synthetic strategies.

In first strategy, use of a pre-formed 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) carbon skeleton consisting of trifluoro methyl benzene ring is substituted with 3 carbon chain at meta position.

In second strategy, 3 carbon chain is introduced at amino group of 3-trifluoromethyl aniline under Heck reaction conditions using allyl alcohol or acrolein.

The first strategy often involves multiple steps and use of hazardous reagents and conditions whereas second strategy involves formation of regio-isomer of 3-[3-(trifluoromethyl) phenyl] propionaldehyde (VII) as by-product, as depicted in Scheme 6.

(Scheme 6)

Presence of regio-isomer of 3-[3-(trifluoromethyl) phenyl] propionaldehyde (VII) in bisulphite adduct results in formation of cinacalcet isomeric impurity (VIII) in cinacalcet, as depicted in Scheme 7.

(Scheme 7)

Removal of isomeric impurity (VIII) is cumbersomely difficult due to its structural similarity with cinacalcet. The inventors of the present invention meticulously designed a synthetic process to obtain bisulphite adduct of more than 99.5% purity, which is used in the preparation of cinacalcet hydrochloride with impurity less than 0.1%, which is within the set limits of ICH guidelines.

In a preferred embodiment of the present invention, the allyl alcohol of formula (VI) is added to a reaction mixture containing starting material 3-trifluromethyl aniline (V), source of nitrous acid and suitable catalyst in a solvent to produce FMPP (III).

Nitrous acid is preferably generated in situ through the reaction of aqueous solution of sodium nitrite (NaNO2) and Sulphuric acid (H2SO4) or hydrochloric acid (HCl).

Catalyst is selected from palladium acetate or palladium chloride and is preferably used in the range of 1.0 to 2.0 percent with respect to 3-trifluromethyl aniline (V).

The reaction is carried out in presence of mixture of solvent consisting acetonitrile and water. Reaction can be carried out at temperature of about 0oC to 35oC.

After completion of the reaction, a water immiscible solvent is charged to reaction mixture. The suitable water immiscible solvents include but not limited to toluene, xylene, heptane or mixtures thereof. Organic layer containing FMPP (III) is converted to its bisulphite adduct (IIIa) by treating with aqueous solution of sodium bisulphite.

Formula (IIIa)

The adduct formation reaction can be advantageously carried out at temperature 25°C to 35°C. The inventors of the present invention found out that by modifying the workup and isolation procedure of bisulphite adduct (IIIa) a very high purity product with more than 99.5% purity is obtained. Use of high purity bisulphite adduct simplifies purification procedure in cinacalcet hydrochloride synthesis and does not necessitates use of high volume of mixture of solvents. In the modified work up and isolation procedure, water is added to reaction mixture whereby bisulphite adduct gets extracted in water leaving impurities in organic layer. From the aqueous layer bisulphite adduct is precipitated out by addition of metal chloride. The separated bisulphite adduct is isolated by filtration resulting in further removal of impurities in aqueous mother liquor.

The metal chloride used to precipitate bisulphite adduct (IIIa) can be selected from sodium chloride, potassium chloride, calcium chloride and the like.

Reductive amination of 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) with R-(+)-1-(1-naphthyl) ethylamine (NEA) (II) in the presence of hydride transfer reagent results in formation of cinacalcet.

The bisulphite adduct (IIIa) is treated with aqueous solution of base in suitable water immiscible solvent to release 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III). Separate layers. To the organic layer an alcoholic solvent selected from group consisting of methyl alcohol, ethyl alcohol, propyl alcohol and isopropyl alcohol is added, followed by R-(+)-1-(1-naphthyl) ethylamine and hydride transfer reagent. The hydride transfer reagent is selected form group consisting of sodium triacetoxy borohydride, sodium borohydride, lithium borohydride and potassium borohydride. The suitable water immiscible solvent is Methylene dichloride (MDC).

The quantity of R-(+)-1-(1-naphthyl) ethylamine used is critical in getting desired quality and output of cinacalcet hydrochloride (I). Sub-optimum quantity results in loss of yield while excess quantity results in contamination of cinacalcet with unreacted R-(+)-1-(1-naphthyl) ethylamine. The inventors of the present invention by doing meticulous laboratory work established that R-(+)-1-(1-naphthyl) ethylamine quantity in the range 1.0 mole equivalent to 1.3 mole equivalent with respect to bisulphite adduct (IIIa) is desirable to get right yield and quality of Cinacalcet.

Cinacalcet obtained is converted in to hydrochloride salt by treatment with hydrogen chloride in ethyl acetate. The cinacalcet hydrochloride obtained is repulped in hot water and filtered. This is optionally followed by crystallization in ethyl acetate. Cinacalcet hydrochloride obtained has HPLC purity more than 99.9% with individual impurities less than 0.10%.

Hereinafter, the present invention will be described in more detail with reference to the following examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.

Example 1
Preparation of sodium {1-hydroxy -3-(3-trifluoromethyl phenyl} sulfonate (IIIa)

3-trifluromethyl aniline (200 gm) is dissolved in acetonitrile (400ml). To the reaction mixture is added aqueous sulfuric acid (1332ml) under cooling followed by sodium nitrite (106 gm). It is further reacted with palladium acetate (4 gm) and allyl alcohol (72 gm). Charged toluene (330 ml) and separate layers. To the organic layer containing 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) is added sodium bisulphite (198 gm) in water (284 ml) at ambient temperature. Allow to settle. Separate layers. Wash aqueous layer with toluene. To the aqueous layer, charge sodium chloride (100gm) under cooling. Filter separated solid, wash with cold water. Dry wet cake to get bisulphite adduct (140.5 gm). Purity by GC – 99.57%.

Example 2
Preparation of N-[1-(R)-(-)-(1-naphyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-1-aminopropane hydrochloride (cinacalcet hydrochloride)

Sodium {1- hydroxy - 3-(3-trifluoromethyl phenyl) propyl} sulfonate (65 gm) obtained in example 1 is treated with 20% aqueous sodium hydroxide (48ml) in MDC (250 ml). Separate layers. To the organic layer is added methanol (139 ml) followed by (R)-(+)-1-(1-naphthyl) ethylamine (39.68 gm) and sodium triacetoxy borohydride (90 gm) under cooling. After the reaction is over, reaction mixture is worked up by adjusting to alkaline pH followed by layer separation. Organic layer is evaporated to get cinacalcet base as oil. It is treated with hydrogen chloride (15 gm) in ethyl acetate (325 ml). The solid obtained is isolated by filtration and dried to give cinacalcet hydrochloride (61 gm). It is repulped in hot water (2000 ml), cooled, filtered to get cinacalcet hydrochloride (72gm), having HPLC purity 98.91%. It is crystallized from ethyl acetate to get cinacalcet hydrochloride (42 gm), having HPLC purity 100%.
Claims:We claim
1. A process for preparing sodium {1-hydroxy-3-(3-trifluoromethyl phenyl) propyl} sulfonate (bisulphite adduct) of formula IIIa

comprising the steps of
(a) adding allyl alcohol (VI) to a reaction mixture of 3-trifluromethyl aniline (V), source of nitrous acid and palladium catalyst

in a mixture of acetonitrile and water at a temperature between 0°C to 35°C to obtain 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III);

(b) extracting 3-[3-(trifluoromethyl) phenyl] propionaldehyde (III) obtained in step (a) in a water immiscible solvent and reacting with aqueous sodium bisulphite;
(c) adding metal chloride to an aqueous layer separated from step (b) and isolating the precipitated bisulphite adduct (IIIa) by filtration.
2. The process as claimed in claim 1, wherein palladium catalyst is selected from a group consisting of palladium acetate and palladium chloride.
3. The process as claimed in claim 1, wherein water immiscible solvent is selected from a group consisting of toluene, xylene, heptane and mixtures thereof.
4. The process as claimed in claim 1, wherein water immiscible solvent is toluene.
5. The process as claimed in claim 1, wherein the metal chloride is selected from a group consisting of sodium chloride, potassium chloride and calcium chloride.
6. An improved process for the preparation of cinacalcet hydrochloride.
7. Sodium {1-hydroxy-3-(3-trifluoromethyl phenyl) propyl} sulfonate (bisulphite adduct) as prepared by claim 1 used for the preparation of cinacalcet hydrochloride.
8. An improved process for the preparation of cinacalcet hydrochloride comprising the steps of
(a) reacting sodium {1-hydroxy-3-(3-trifluoromethyl phenyl) propyl} sulfonate (bisulphite adduct) of formula IIIa with aqueous alkali in a water immiscible solvent;
(b) mixing a solvent selected from a group consisting of methyl alcohol, ethyl alcohol, propyl alcohol and isopropyl alcohol to an organic layer separated from step (a) and reacting with 1.0 to 1.3 mole equivalent of (R)-(+)-1-(1-naphthyl) ethyl amine (II)

in the presence of hydride transfer agent selected from a group consisting of sodium triacetoxy borohydride, sodium borohydride, lithium borohydride and potassium borohydride to obtain cinacalcet (Ia);

(c) reacting cinacalcet obtained in step (b) with hydrogen chloride in ethyl acetate to obtain cinacalcet hydrochloride;
(d) repulping cinacalcet hydrochloride obtained in step (c) in hot water; and
(e) filtering cinacalcet hydrochloride obtained in step (d) to isolate solid cinacalcet hydrochloride
9. The process as claimed in claim 8 optionally comprises a step of crystallizing cinacalcet hydrochloride obtained in step (e).