DESCRIPTION

The present invention provides a process for the preparation of Cinacalcet or its pharmaceutically acceptable salt  which comprises a single step reaction of 3-[3-(Trifluoromethyl)phenyl]propionaldehyde with (R)-(1-naphthyl)ethylamine using a reducing agent in presence of zinc salt and alcohol.

Cinacalcet Hydrochloride of Formula I is chemically known as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3(trifluoromethyl)phenyl]-1-aminopropane hydrochloride.

Formula I

Cinacalcet hydrochloride (Sensipar®) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Cinacalcet hydrochloride is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with Cinacalcet hydrochloride lowers serum levels of PTH as well as the calcium/phosphorus ion product  a measure of the amount of calcium and phosphorus in the blood.

U.S. patent no. 6 211 244 discloses Cinacalcet and its pharmaceutical acceptable salts. Further  the ""244 patent discloses process for preparing Cinacalcet which involves reaction of 1-acetylnaphthalene with 3-[3(trifloromethyl)phenyl]propylamine in the presence of titanium isopropoxide to produce an cinacalcet isoimine  followed by treatment with sodium cyanoborohydride in methanol and resolution of the racemic cinacalcet base by chiral liquid chromatography.

Drug of the future  2002  27(9)  831-836 discloses a process for preparing Cinacalcet which involves reaction of (R)-(1-naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium tetraisopropoxide to give cinacalcet imine  which is then reduced with sodium cyanoborohydride in ethanol

Various other references  for example  WO 06/125026  WO 2008/068625  WO 2007/127445  WO 2008/035381  WO 2008/058235  WO2008/058236  WO 2008/117299  WO 2009/153814  WO 2009/002427  US 2011/124917A1; disclose processes for the preparation of Cinacalcet.

The above processes involve use of number of steps to provide Cinacalcet which affects yield of Cinacalcet and production time. The present inventors found surprising positive affect for yield and production time of Cinacalcet by the use of sodium cyanoborohydride in presence of zinc salt and alcohol. The present inventors also found that the reactivity of reducing agent  sodium cyanoborohydride  enhances for the single step reductive amination in the presence of certain additives like zinc salt  for example  zinc chloride.

In one aspect of the present provides a single step process for Cinacalcet of Formula II or salt thereof

Formula II
comprises reductive amination of 3-[3-(trifluoromethyl)phenyl]propionaldehyde of formula III
Formula III
by reaction with (R)-(1-naphthyl)ethylamine of formula IV or salt thereof

Formula IV
using a reducing agent  sodium cyanoborohydride  in presence of zinc salt and alcohol.

The reducing agent used is not only sodium cyanoborohydride  but also it includes sodium triacetoxyborohydride  Ti(iPrO)4  and the like for the reductive amination in the presence of zinc salt and alcohol.

A salt of Cinacalcet or (R)-(1-naphthyl)ethylamine is preferably a pharmaceutically acceptable salt  for example  the hydrochloride  hydrobromide  maleate  sulfate  phosphate  sulfamate  acetate  citrate and tartrate  preferably the hydrochloride salt.

The reaction may be conducted in presence of acid along with zinc salt to improve the reductive amination to provide cinacalcet. The acid includes formic acid  citric acid  trifluoroacetic acid and the like. The zinc slat is zinc chloride  zinc bromide and the like. The quantity of Zinc salt used for the reaction is about 0.1 to about 0.2 molar equivalents per the molar equivalent of (R)-(1-naphthyl)ethylamine or salt thereof to enhance the reaction conditions.

The quantity of reducing agent  sodium cyanoborohydride  used for the reductive amination reaction may range from 0.8 to 1.3 molar equivalents per the molar equivalent of (R)-(1-naphthyl)ethylamine or salt thereof.

The present invention involves drop wise addition of diluted 3-[3-(trifluoromethyl)phenyl]propionaldehyde in alcohol to the reaction mixture for a period of 5 to 30 minutes or more.

The reductive amination reaction is carried out in presence of straight and branched C1-C6 alcohols such as methanol  ethanol  propyl alcohol and the like at a suitable temperature from about 20 to about 40°C. The reaction may be maintained for a period of 10 to 30 minutes or more to complete the production of Cinacalcet or salt thereof.

After completion of the reaction  the cinacalcet or salt thereof may be recovered by using conventional methods such as acid and base extractions  and the like.

The yield of Cinacalcet or salt thereof obtained by the process of the present invention is more than or equal to 95%. The process of the present invention is simple  industrial feasible and provides high yield and reduces the formation of byproducts and impurities.

The present invention also provides a process for a pharmaceutically acceptable salt of cinacalcet  which comprises dissolving the free base in alcohol and then reacting with acid  for example  hydrochloric acid  sulfuric acid  phosphoric acid  acetic acid  citric acid and tartaric acid and the like.

In an embodiment  the present invention provides a process for preparing Cinacalcet Hydrochloride comprising dissolving cinacalcet in alcohol followed by treating with hydrochloric acid. The Hydrochloric acid may be aqueous or organic or gaseous acid.

The pharmaceutically acceptable salt of cinacalcet may be recovered by the known methods  for example  by filtration and then dried at elevated temperatures.

The present invention provides a process for purifying Cinacalcet or salt thereof comprises suspension of cinacalcet or salt thereof in a solvent and then stirring it at 30°C to 45 °C for sufficient time period  for example  10 minutes to 3 hours to affect the purity of cinacalcet or sat theroef. The solvent is selected from nitrile solvent such ad acetonitrile  and the like; esters such as ethyl acetate  and the like; chlorinated solvents such as dichloromethane  chlorobenzene and the like.

In an embodiment  the present invention provides a process for the purification of cinacalcet hydrochloride  which comprises
a) suspending cinacalcet hydrochloride in a nitrile solvent;
b) stirring the suspension of step a) at 30°C to 45 °C; and
c) recovering pure cinacalcet hydrochloride.

The suspension may be prepared by the addition of cinacalcet hydrochloride in a nitrile solvent at a room temperature or may be taken from the previous step and then subjected the suspension for heating to reach the temperature of about 30 to about 45°C. The resultant reaction mixture stirred for sufficient time period  for example  10 minutes to 3 hours at the same temperature to affect the purity of cinacalcet hydrochloride.

The purified cinacalcet hydrochloride may be recovered by the known methods  for example  by cooling the reaction mixture to below room temperature and then filtering it to afford the purity of cinacalcet hydrochloride greater than or equal to 99.8% determined by HPLC.

The present invention is further illustrated by the following example  which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES
Example -1
A process for preparing Cinacalcet
To a stirred solution of (R)-(1-naphthyl)ethylamine (1.1 molar equivalent)  sodium cyanoborohydride (1.1 molar equivalent)  zinc chloride (0.15 molar equivalent) and formic acid (for maintaining pH 6.5-6.8) in methanol  the solution of 3-[3-(trifluoromethyl) phenyl] propanal in methanol was added drop wise at room temperature. After completion of reaction  dichloromethane was added and pH of reaction mixture was adjusted to below 1 using concentrated hydrochloric acid. The layers were separated. The organic phase was washed with water. The pH of the reaction mixture was adjusted to ~14 using dilute aq. NaOH solution after adding fresh water. The organic layer was separated  washed with water and concentrated at reduce pressure to give Cinacalcet.

Yield: 95%

Example-2:
A process for preparing Cinacalcet Hydrochloride
1N. hydrochloric acid was added (up to pH 2.5-3.5) slowly to the solution of Cinacalcet in methanol and then stirred for one hour. The precipitated solid was filtered  washed with water and dried in vacuum oven at 55-60°C to get cinacalcet hydrochloride.

Yield: 85%
Purity: 96%

Example-3:
Purification of Cinacalcet hydrochloride
Cinacalcet hydrochloride was suspended in acetonitrile and then stirred at 35-40°c for 3 hours. The reaction mixture was cooled and then filtered. The obtained solid was washed with acetonitrile and dried to obtain Cinacalcet hydrochloride.

Yield: 0.90 w/w.
Purity: 99.8%

We Claim:

1. A single step process for Cinacalcet of Formula II or salt thereof

Formula II
comprises reductive amination of 3-[3-(trifluoromethyl)phenyl]propionaldehyde of formula III
Formula III
by reaction with (R)-(1-naphthyl)ethylamine of formula IV or salt thereof

Formula IV
using a reducing agent  sodium cyanoborohydride  in presence of zinc salt and alcohol.

2. The process of claim 1  wherein said salt is hydrochloride.

3. The process of claim 1  wherein said reductive amination reaction is conducted in presence of acid.

4. The process of claim 1  wherein said zinc salt is zinc chloride.

5. The process of claim 1  wherein said reducing agent is about 1.1 molar equivalents per the molar equivalent of (R)-(1-naphthyl)ethylamine or salt thereof.

6. The process of claim 1  wherein said cinacalcet or salt thereof is further converted to cinacalcet hydrochloride.

7. A process for the purification of cinacalcet hydrochloride  which comprises:
a) suspending cinacalcet hydrochloride in a nitrile solvent;
b) stirring the suspension of step a) at 30°C to 45 °C; and
c) recovering pure cinacalcet hydrochloride.

8. The process of claim 7  wherein said nitrile solvent is acetonitrile.

9. The process of claim 7  wherein said pure cinacalcet hydrochloride is having greater than or equal to 99.8% determined by HPLC.

Dated this 30th day of November 2012 For Wockhardt Limited

(Dr. Mandar Kodgule)
Authorized Signatory