WO2012007954A1 - Process for cinacalcet hydrochloride - Google Patents

Process for cinacalcet hydrochloride Download PDF

Info

Publication number
WO2012007954A1
WO2012007954A1 PCT/IN2010/000477 IN2010000477W WO2012007954A1 WO 2012007954 A1 WO2012007954 A1 WO 2012007954A1 IN 2010000477 W IN2010000477 W IN 2010000477W WO 2012007954 A1 WO2012007954 A1 WO 2012007954A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
solvent
ether
trifluoromethyl
phenyl
Prior art date
Application number
PCT/IN2010/000477
Other languages
French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Rapolu Raji Reddy
Jambula Mukunda Reddy
Bandi Vamsi Krishna
Original Assignee
Hetero Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hetero Research Foundation filed Critical Hetero Research Foundation
Priority to PCT/IN2010/000477 priority Critical patent/WO2012007954A1/en
Priority to EP10854669.8A priority patent/EP2593422B1/en
Priority to US13/810,319 priority patent/US8921606B2/en
Publication of WO2012007954A1 publication Critical patent/WO2012007954A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/41—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrogenolysis or reduction of carboxylic groups or functional derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/70—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by reduction of unsaturated amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification

Definitions

  • 3-[3-(Trifluoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride.
  • the present invention provides a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde.
  • the present invention also provides an improved process for preparation of cinacalcet hydrochloride in high yields.
  • the present invention further provides a process for purification of cinacalcet hydrochloride.
  • Calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone ("PTH") by activating calcium receptors.
  • the secretion of PTH is normally regulated by the calcium-sensing receptor.
  • Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours.
  • Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH, an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.
  • 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. Cinacalcet hydrochloride is marketed as Sensipar ® in USA and as Mimpara ® in Europe.
  • Cinacalcet and its pharmaceutical acceptable salts were disclosed in U.S. patent no. 6,21 1 ,244 (herein after referred to as the '244 patent).
  • cinacalcet can prepared by reacting 1-acethylnaphthalene 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.
  • the synthetic procedure is illustrated in scheme I, below:
  • cinacalcet can be prepared by reacting 3- fluoromethylcinnamonitrile with diisobutyl aluminum hydride to give aluminum-imine intermediate, which was then reacted with (R)-l-(l-naphthyl)ethylamine, and reducing the cinacalcet imine intermediate thus obtained with sodium cyanoborohydride in ethanol.
  • cinacalcet can be prepared by reacting (R)-(l-naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium tetraisopropoxide to give cinacalcet imine, which was then reduced with sodium cyanoborohydride in ethanol.
  • Scheme II The synthetic procedure was illustrated in scheme II, below:
  • 3-[3- (trifluoromethyl)phenyl]propionaldehyde can be prepared by reacting 3-[3- (trifluoromethyl)phenyl]propan- 1 -ol with 2,2,6,6-tetramethylpiperidine- 1 -oxyl (TEMPO) and sodium hypochlorite in the presence of potassium bromide in methylene chloride.
  • TEMPO 2,2,6,6-tetramethylpiperidine- 1 -oxyl
  • PCT publication WO 2008/068625 disclosed a process for the preparation of cinacalcet by reductive amination of 3-(3-trifluoromethylphenyl)propanal with (R)-l- naphthylethylamine in the presence of a sodium triacetoxyborohydride.
  • PCT publication WO 2007/127445 disclosed a process for the preparation of cinacalcet by reacting 3-(3-trifluoromethylphenyl)propanoic acid with R)-l- naphthylethylamine to give N-[(lR)-l-(l-napthyl)ethyi]-3-(3- trifluoromethyl)phenyl]propanamide, which was then reduced to give cinacalcet and its pharmaceutically acceptable salts.
  • Similar process was also discribed in PCT publications WO 2008/035381, WO 2008/058235, WO 2008/1 17299; Tetrahedron Letters 2008 49(1), 13-15 and Synthetic communications 2008 38(10), 1512-1517.
  • cinacalcet can be prepared by reacting (R)-l- naphthylethylamine with 3-(3-trifluoromethylphenyl)propenaldehyde to give the non isolated (R)-N- [3 - [3 -(trifluoromrthyl)phenyl] -2-propenylimino-N- [ 1 -( 1 - napththyl)ethylamine, which was then reduced with sodium borohydride in methanol and hydrogenating the cinacalcet imine intermediate thus obtained.
  • 3-[3-(Trifluoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride.
  • 3-[3-(trifluoromethyl)phenyl]propionaldehyde can prepared from ester of 3-[3-(trifluoromethyl)phenyl]propionic acid in a single step. It has been found that the ester of 3-[3-(trifluoromethyl)phenyl]propionic acid can be reduced selectively to the corresponding aldehyde by choosing suitable reaction condition, avoiding the formation of excess of the undesired corresponding alcohol.
  • the present invention is intended to enhance the purity of cinacalcet hydrochloride.
  • the present invention is directed to reduce or remove 2-[3- (trifluoromethyl)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-hydroxy pentanal and (R)-l- (naphthyl)ethylamine impurities from cinacalcet hydrochloride.
  • one object of the present invention is to provide a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde.
  • Another object of the present invention is to provide an improved process for the preparation of cinacalcet hydrochloride.
  • Yet another object of the present invention is to provide a process for the purification of cinacalcet hydrochloride.
  • the present invention provided a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde of formula I,
  • R' is lower alkyl
  • DIBAL-H diisobutylaluminium hydride
  • the present invention provided a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde, which comprises:
  • DIBAL-H diisobutylaluminium hydride
  • step (b) adding ethyl acetate to the reaction mass obtained in step (b);
  • the present invention provided an improved process for the preparation of cinacalcet hydrochloride in high yields, which comprises:
  • step (c) adding ether solvent, hydrochloride in an organic solvent and water to the residual mass obtained in step (c);
  • the present invention provided a process for the purification of cinacalcet hydrochloride, which comprises:
  • room temperature refers to temperature at about 25 to 35°C.
  • R' is lower alkyl
  • DIBAL-H diisobutylaluminium hydride
  • lower alkyl refers to Ci - C 4 alkyl.
  • alkyl may be selected from methyl or ethyl, and more preferable alkyl is methyl.
  • the solvent used in the process may preferably be selected from the group consisting of cyclohexane, cyclohexene, cycloheptane, cyclopentane, n-hexane, n- heptane, benzene, toluene, xylene, dichloromethane, chloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1 ,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme
  • solvents are n-hexane, cyclohexane, toluene, dichloromethane, diisopropyl ether and tetrahydrofuran, and still more preferable solvents are n-hexane, toluene, dichloromethane and tetrahydrofuran.
  • the reaction mass may preferably be maintained in the process below -50°C and more preferable at about -70 to -85°C.
  • DIBAL-H diisobutylaluminium hydride
  • step (b) adding ethyl acetate to the reaction mass obtained in step (b);
  • the solvent used in step (a) may preferably be selected from the group consisting of cyclohexane, cyclohexene, cycloheptane, cyclopentane, n-hexane, n-heptane, benzene, toluene, xylene, dichloromethane, chloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1 ,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane.
  • More preferable solvents are n-hexane, cyclohexane, toluene, dichloromethane, diisopropyl ether and tetrahydrofuran, and still more preferable solvents are n-hexane, toluene, dichloromethane and tetrahydrofuran.
  • the reaction mass may preferably be maintained in step (a) below -50°C and more preferable at about -70 to -85°C.
  • the alcohol solvent used in step (b) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, isobutanol and n-butanol, and more preferable alcohol solvent is methanol.
  • the separated solids may be collected by the method known such as centrifugation or filtration.
  • Isolation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde in step (e) can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent and the like.
  • an improved process for the preparation of cinacalcet hydrochloride in high yields which comprises:
  • step (a) reacting sodium cyanoborohydride with the reaction mass obtained in step (a); c) concentrating the reaction mass;
  • step (c) adding ether solvent, hydrochloride in an organic solvent and water to the residual mass obtained in step (c);
  • the ether solvent used in step (a) may preferably be a solvent or mixture of solvents selected from tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1 ,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane, and more preferable ether solvents are tetrahydrofuran and diisopropyl ether.
  • step (a) may preferably be carried out at below -20°C and more preferable at about -30 to -60°C
  • the reaction mass is concentrated in step (c) by distilling off the solvent.
  • the distilling off the solvent may be carried out at atmospheric pressure or at reduced pressure.
  • the distillation may preferably be carried out until the solvent is almost completely distilled off.
  • the ether solvent used in step (d) may preferably be a solvent or mixture of solvents selected from tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane, and more preferable ether solvents are tetrahydrofuran and diisopropyl ether.
  • the organic solvent used in step (d) may preferably be a solvent or mixture of solvents selected from the group consisting of an ether solvents such as tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane; an ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate. More preferable organic solvents are diisopropyl ether and ethyl acetate, still more preferable organic solvent is ethyl acetate.
  • an ether solvents such as tetrahydrofuran,
  • Cinacalcet hydrochloride may be isolated in step (e) by methods known such as filtration or centrifugation.
  • substantially pure cinacalcet hydrochloride refers to cinacalcet hydrochloride having the purity greater than about 98% by weight, preferably greater than about 99% by weight, and more preferably greater than about 99.5% by weight.
  • the alcohol solvent used in step (a) may preferably be selected from methanol, ethanol, isopropyl alcohol, isobutanol or n-butanol, and more preferable alcohol solvent is methanol.
  • the nitrile solvent used in step (a) may preferably be selected from acetonitrile, propionitrile, butyronitrile or benzonitrile, and more preferable nitrile solvent is acetonitrile.
  • the step (a) is preferably carried out at elevated temperature.
  • elevated temperature refers to temperature at above 25°C. More preferably the step (a) is carried out at about 40 to 100°C and still more preferably at about 45 to 90°C.
  • Isolation of highly pure cinacalcet hydrochloride may preferably be carried out by methods known such as filtration or centrifugation.
  • the purification process yields cinacalcet hydrochloride with reduced levels of impurities, specifically, 2- [3 -(trifluoromethyl)phenyl]-5 - [3 -(trifluoromethyl)phenyl] -3 - hydroxy pentanal and (R)-l-(naphthyl)ethylamine.
  • the purity of cinacalcet hydrochloride is measured by High performance liquid chromatography (HPLC).
  • Palladium carbon (10%, 6 gm) was added to water (20 ml) and then added 3- (trifluoromethyl)cinnamic acid (100 gm) and toluene (1000 ml).
  • the resulting contents were hydrogenated with hydrogen gas at a pressure of 4 kg at 45 to 50°C for 2 hour 30 minutes.
  • the reaction mass was then filtered through celite bed and the layers were separated.
  • the organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 98.7 gm of 3-[3-(trifluoromethyl)phenyl]propionic acid.
  • 3-[3-(Trifluoromethyl)phenyl]propionic acid (100 gm) as obtained in example 1 was dissolved in methanol (250 ml) and then added concentrated sulfuric acid (45 gm) slowly for 25 minutes. The temperature of the reaction mass was raised to 40 to 45°C and maintained for 1 hour at 30 to 45°C. The methanol solvent was distilled off under vacuum at below 45°C to obtain residual mass. To the residual mass was added water (600 ml) and methylene dichloride (500 ml). The separated organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 99.2 gm of methyl 3-[3-(trifluoromethyl)phenyl]propanoate.
  • Methyl 3-[3-(trifluoromethyl)phenyl]propanoate (5 gm) as obtained in example 2 was added to toluene (50 ml) and then cooled to -75 to -80°C.
  • a solution of diisobutylaluminium hydride (4.59 gm) in n-hexane (33 ml) slowly for 1 hour 30 minutes at -75 to -80°C.
  • the reaction mass was maintained for 1 hour at -75 to - 80°C and then added methanol (5 ml) at -75 to -80°C.
  • the temperature of the reaction mass was raised to 0°C and the reaction mass was poured to the chilled water (150 ml).
  • reaction mass was stirred for 15 minutes at -45 to -50°C and then added a solution of sodium cyanoborohydride (4 gm) in methanol (40 ml) slowly for 20 minutes.
  • the temperature of the reaction mass was raised to room temperature and maintained for 2 hours at room temperature.
  • water 50 ml
  • reaction mass was then filtered through celite bed. The layers were separated and the aqueous layer was extracted with diisopropyl ether.
  • the combined organic layer was dried and the solvent was distilled off under reduced pressure to obtain residual mass.
  • diisopropyl ether 80 ml
  • water 100 ml
  • Cinacalcet hydrochloride 98.5%
  • reaction mass was stirred for 20 minutes at -45 to -50°C and then added a solution of sodium cyanoborohydride (2 gm) in methanol (20 ml) slowly for 20 minutes.
  • the temperature of the reaction mass was raised to room temperature and maintained for 2 hours at room temperature.
  • water 25 ml
  • reaction mass was then filtered through celite bed. The layers were separated and the aqueous layer was extracted with diisopropyl ether.
  • the combined organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain residual mass.
  • diisopropyl ether 40 ml
  • water 50 ml
  • Cinacalcet hydrochloride 98.6%; 2- [3 -(Trifluoromethyl)phenyl] -5- [3 -(trifluoromethyl)phenyl] -3 -hydroxy pentanal impurity: 1.05%;
  • reaction mass was stirred for 15 minutes at -45 to -50°C and then added a solution of sodium cyanoborohydride (40 gm) in methanol (380 ml) slowly for 20 minutes.
  • the temperature of the reaction mass was raised to room temperature and maintained for 2 hours at room temperature.
  • water 450 ml
  • reaction mass was then filtered through celite bed.
  • the layers were separated and the aqueous layer was extracted with diisopropyl ether.
  • the combined organic layer was dried and the solvent was distilled off under reduced pressure to obtain residual mass.
  • diisopropyl ether 700 ml
  • water 1000 ml
  • Cinacalcet hydrochloride 98.5%
  • Cinacalcet hydrochloride (10 gm) as obtained in example 4 was dissolved in a mixture of water (125 ml) and methanol (15 ml). The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried at 60 to 65°C for 6 hours to obtain 9.2 gm of substantially pure cinacalcet hydrochloride.
  • Cinacalcet hydrochloride 99.96%
  • Cinacalcet hydrochloride (10 gm) was suspended in a mixture of water (80 ml) and acetonitrile (20 ml). The contents were heated to 80°C and stirred for 20 minutes at
  • Cinacalcet hydrochloride 99.6%
  • Cinacalcet hydrochloride (10 gm) was dissolved in methanol (15 ml). To the solution was added water (125 ml) slowly for 40 minutes to form precipitation. The reaction mass was stirred for 2 hour at room temperature and filtered. The solid obtained was dried to obtain 9.3 gm of substantially pure cinacalcet hydrochloride.
  • Cinacalcet hydrochloride 99.98%

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

3-[3-(Trifluoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride. The present invention provides a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde. The present invention also provides an improved process for preparation of cinacalcet hydrochloride in high yields. The present invention further provides a process for purification of cinacalcet hydrochloride.

Description

PROCESS FOR CINACALCET HYDROCHLORIDE
Field of the Invention
3-[3-(Trifluoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride. The present invention provides a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde. The present invention also provides an improved process for preparation of cinacalcet hydrochloride in high yields. The present invention further provides a process for purification of cinacalcet hydrochloride.
Background of the Invention
Cinacalcet hydrochloride is chemically, (R)-a-methyl-N-[3-[3- trifluoromethyl)phenyl]propyl]-l-napthalenemethanamine hydrochloride. Cinacalcet hydrochloride is represented by the following structure:
Figure imgf000002_0001
Calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone ("PTH") by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH, an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death.
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. Cinacalcet hydrochloride is marketed as Sensipar® in USA and as Mimpara® in Europe.
Cinacalcet and its pharmaceutical acceptable salts were disclosed in U.S. patent no. 6,21 1 ,244 (herein after referred to as the '244 patent). In accordance with the '244 patent, cinacalcet can prepared by reacting 1-acethylnaphthalene 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. The synthetic procedure is illustrated in scheme I, below:
Figure imgf000003_0001
1 -acetyl naphthalene 3-[3-(trifluoromethyl)phenyl]- propyl amine
Sodium cyanoborohydride
Methanol
Figure imgf000003_0002
cinacalcet iso-imine
Chiral LC
(R)-cinacalcet base
Figure imgf000003_0003
racemic cinacalcet base
Scheme I According to the '244 patent, cinacalcet can be prepared by reacting 3- fluoromethylcinnamonitrile with diisobutyl aluminum hydride to give aluminum-imine intermediate, which was then reacted with (R)-l-(l-naphthyl)ethylamine, and reducing the cinacalcet imine intermediate thus obtained with sodium cyanoborohydride in ethanol.
Process for the preparation of cinacalcet was reported in Drug of the future, 2002, 27(9), 831-836. According to the journal, cinacalcet can be prepared by reacting (R)-(l-naphthyl)ethylamine with 3-[3-(trifluoromethyl)phenyl]propionaldehyde in the presence of titanium tetraisopropoxide to give cinacalcet imine, which was then reduced with sodium cyanoborohydride in ethanol. The synthetic procedure was illustrated in scheme II, below:
Figure imgf000004_0001
3-[3-(trifluoromethyl)phi 1 (R)- 1 -( 1 -naphtyl)ethy lamine
propionaldehyde
Sodium cyanoborohydride
(R)-cinacalcet base Ethanol
Figure imgf000004_0002
cinacalcet imine
Scheme II
Process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde was reported in Tetrahedron letters, (45), 8355-8358, (2004) footnote 12. According to the journal, 3-[3-(trifluoromethyl)phenyl]propionaldehyde can be prepared by reduction of 3-(trifluoromethyl)cinnamic acid to the corresponding alcohol followed by swern oxidation to give the desired aldehyde. The synthetic procedure was illustrated in scheme III, below:
Figure imgf000004_0003
3-[3-(trifluoromethyl)phenyl]- propionaldehyde
Scheme III PCT publication WO 2008/035212 disclosed a process for preparing 3-[3- (trifluoromethyl)phenyl]propionaldehyde. According to the publication, 3-[3- (trifluoromethyl)phenyl]propionaldehyde can be prepared by reacting 3-[3- (trifluoromethyl)phenyl]propan- 1 -ol with 2,2,6,6-tetramethylpiperidine- 1 -oxyl (TEMPO) and sodium hypochlorite in the presence of potassium bromide in methylene chloride.
PCT publication WO 2008/068625 disclosed a process for the preparation of cinacalcet by reductive amination of 3-(3-trifluoromethylphenyl)propanal with (R)-l- naphthylethylamine in the presence of a sodium triacetoxyborohydride.
PCT publication WO 2007/127445 disclosed a process for the preparation of cinacalcet by reacting 3-(3-trifluoromethylphenyl)propanoic acid with R)-l- naphthylethylamine to give N-[(lR)-l-(l-napthyl)ethyi]-3-(3- trifluoromethyl)phenyl]propanamide, which was then reduced to give cinacalcet and its pharmaceutically acceptable salts. Similar process was also discribed in PCT publications WO 2008/035381, WO 2008/058235, WO 2008/1 17299; Tetrahedron Letters 2008 49(1), 13-15 and Synthetic communications 2008 38(10), 1512-1517.
PCT publication WO 2009/153814 disclosed a process for the preparation of cinacalcet. According to the publication, cinacalcet can be prepared by reacting (R)-l- naphthylethylamine with 3-(3-trifluoromethylphenyl)propenaldehyde to give the non isolated (R)-N- [3 - [3 -(trifluoromrthyl)phenyl] -2-propenylimino-N- [ 1 -( 1 - napththyl)ethylamine, which was then reduced with sodium borohydride in methanol and hydrogenating the cinacalcet imine intermediate thus obtained.
3-[3-(Trifluoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride.
The major problem with the direct preparation of the 3-[3-
(trifluoromethyl)phenyl]propionaldehyde from an ester of 3-[3- (trifluoromethyl)phenyl]propionic acid is that the question of reproducibility of the aldehyde formation when used the reagents such as oxalyl chloride. Another problem with this conversation is that the over reduction of the aldehyde formed to the corresponding undesired alcohol. The present invention makes now available a more efficient process for the manufacture of cinacalcet hydrochloride in particular by providing efficient manufacture of 3-[3-(trifluoromethyl)phenyl]propionaldehyde. According to the present invention, 3-[3-(trifluoromethyl)phenyl]propionaldehyde can prepared from ester of 3-[3-(trifluoromethyl)phenyl]propionic acid in a single step. It has been found that the ester of 3-[3-(trifluoromethyl)phenyl]propionic acid can be reduced selectively to the corresponding aldehyde by choosing suitable reaction condition, avoiding the formation of excess of the undesired corresponding alcohol.
2- [3 -(Trifluoromethyl)phenyl] -5 - [3 -(trifluoromethyl)phenyl] -3-hydroxy pentanal and (R)-l-(naphthyl)ethylamine are potential impurities in cinacalcet hydrochloride.
The chemical formula of (R)-l-(naphthyl)ethylamine may be represented as:
Figure imgf000006_0001
The chemical formula of 2-[3-(trifluoromethyl)phenyl]-5-[3- (trifiuoromethyl)phenyl] -3 -hydroxy pentanal may be represented as:
Figure imgf000006_0002
The present invention is intended to enhance the purity of cinacalcet hydrochloride. In particular, the present invention is directed to reduce or remove 2-[3- (trifluoromethyl)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-hydroxy pentanal and (R)-l- (naphthyl)ethylamine impurities from cinacalcet hydrochloride.
Thus, one object of the present invention is to provide a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde.
Another object of the present invention is to provide an improved process for the preparation of cinacalcet hydrochloride.
Yet another object of the present invention is to provide a process for the purification of cinacalcet hydrochloride. Summery of the Invention
In one aspect, the present invention provided a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde of formula I,
Figure imgf000007_0001
which comprises, reducing the methyl 3-[3-(trifluoromethyl)phenyl]propanoate of formula II
Figure imgf000007_0002
wherein R' is lower alkyl.
with diisobutylaluminium hydride (DIBAL-H) in an hydrocarbon solvent, an chlorinated solvent, an ether solvent or mixtures thereof below -40°C to obtain a compound of formula I.
In another aspect, the present invention provided a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde, which comprises:
a) reducing the methyl 3-[3-(trifluoromethyl)phenyl]propanoate with diisobutylaluminium hydride (DIBAL-H) in an hydrocarbon solvent, an chlorinated solvent, an ether solvent or mixtures thereof below -40°C;
b) quenching the reaction mass with an alcohol solvent;
c) adding ethyl acetate to the reaction mass obtained in step (b);
d) separating out the solids; and
e) isolating 3-[3-(trifluoromethyl)phenyl]propionaldehyde from the mother liquor.
In another aspect, the present invention provided an improved process for the preparation of cinacalcet hydrochloride in high yields, which comprises:
a) adding 3-[3-(trifluoromethyl)phenyl]propionaldehyde to (R)-(l- naphthyl)ethylamine in ether solvent in the presence of titanium(IV)isopropoxide below -5UC; b) reacting sodium cyanoborohydride with the reaction mass obtained in step (a); c) concentrating the reaction mass;
d) adding ether solvent, hydrochloride in an organic solvent and water to the residual mass obtained in step (c); and
e) isolating cinacalcet hydrochloride.
Yet another aspect, the present invention provided a process for the purification of cinacalcet hydrochloride, which comprises:
a) stirring cinacalcet hydrochloride with a solvent system comprising water and solvent selected from alcohol solvent, nitrile solvent and mixture thereof; and b) isolating substantially pure cinacalcet hydrochloride.
Detailed Description of the Invention
The term "room temperature" refers to temperature at about 25 to 35°C.
According to one aspect of the present invention, there is provided a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde of formula
I,
Figure imgf000008_0001
which comprises, reducing the methyl 3-[3-(trifluoromethyl)phenyl]propanoate formula II
Figure imgf000008_0002
wherein R' is lower alkyl.
with diisobutylaluminium hydride (DIBAL-H) in an hydrocarbon solvent, an chlorinated solvent, an ether solvent or mixtures thereof below -40°C to obtain a compound of formula I.
The term "lower alkyl" refers to Ci - C4 alkyl. Preferably alkyl may be selected from methyl or ethyl, and more preferable alkyl is methyl. The solvent used in the process may preferably be selected from the group consisting of cyclohexane, cyclohexene, cycloheptane, cyclopentane, n-hexane, n- heptane, benzene, toluene, xylene, dichloromethane, chloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1 ,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxy ethane. More preferable solvents are n-hexane, cyclohexane, toluene, dichloromethane, diisopropyl ether and tetrahydrofuran, and still more preferable solvents are n-hexane, toluene, dichloromethane and tetrahydrofuran.
The reaction mass may preferably be maintained in the process below -50°C and more preferable at about -70 to -85°C.
According to another aspect of the present invention, there is provided a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde, which comprises:
a) reducing the methyl 3-[3-(trifluoromethyl)phenyl]propanoate with diisobutylaluminium hydride (DIBAL-H) in an hydrocarbon solvent, an chlorinated solvent, an ether solvent or mixtures thereof below -40°C;
b) quenching the reaction mass with an alcohol solvent;
c) adding ethyl acetate to the reaction mass obtained in step (b);
d) separating out the solids; and
e) isolating 3-[3-(trifluoromethyl)phenyl]propionaldehyde from the mother liquor.
The solvent used in step (a) may preferably be selected from the group consisting of cyclohexane, cyclohexene, cycloheptane, cyclopentane, n-hexane, n-heptane, benzene, toluene, xylene, dichloromethane, chloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1 ,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane. More preferable solvents are n-hexane, cyclohexane, toluene, dichloromethane, diisopropyl ether and tetrahydrofuran, and still more preferable solvents are n-hexane, toluene, dichloromethane and tetrahydrofuran. The reaction mass may preferably be maintained in step (a) below -50°C and more preferable at about -70 to -85°C.
The alcohol solvent used in step (b) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, isobutanol and n-butanol, and more preferable alcohol solvent is methanol.
The separated solids may be collected by the method known such as centrifugation or filtration.
Isolation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde in step (e) can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent and the like.
According to another aspect of the present invention, there is provided an improved process for the preparation of cinacalcet hydrochloride in high yields, which comprises:
a) adding 3-[3-(trifluoromethyl)phenyl]propionaldehyde to (R)-(l- naphthyl)ethylamine in ether solvent in the presence of titanium(IV)isopropoxide below -5°C;
b) reacting sodium cyanoborohydride with the reaction mass obtained in step (a); c) concentrating the reaction mass;
d) adding ether solvent, hydrochloride in an organic solvent and water to the residual mass obtained in step (c); and
e) isolating cinacalcet hydrochloride.
The ether solvent used in step (a) may preferably be a solvent or mixture of solvents selected from tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1 ,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane, and more preferable ether solvents are tetrahydrofuran and diisopropyl ether.
The reaction in step (a) may preferably be carried out at below -20°C and more preferable at about -30 to -60°C
Preferably the reaction mass is concentrated in step (c) by distilling off the solvent. The distilling off the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
The ether solvent used in step (d) may preferably be a solvent or mixture of solvents selected from tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane, and more preferable ether solvents are tetrahydrofuran and diisopropyl ether.
The organic solvent used in step (d) may preferably be a solvent or mixture of solvents selected from the group consisting of an ether solvents such as tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxyethane; an ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate. More preferable organic solvents are diisopropyl ether and ethyl acetate, still more preferable organic solvent is ethyl acetate.
Cinacalcet hydrochloride may be isolated in step (e) by methods known such as filtration or centrifugation.
According to another aspect of the present invention, there is provides a process for the purification of cinacalcet hydrochloride, which comprises:
a) stirring cinacalcet hydrochloride with a solvent system comprising water and solvent selected from alcohol solvent, nitrile solvent and mixture thereof; and b) isolating substantially pure cinacalcet hydrochloride.
The term "substantially pure cinacalcet hydrochloride" refers to cinacalcet hydrochloride having the purity greater than about 98% by weight, preferably greater than about 99% by weight, and more preferably greater than about 99.5% by weight.
The alcohol solvent used in step (a) may preferably be selected from methanol, ethanol, isopropyl alcohol, isobutanol or n-butanol, and more preferable alcohol solvent is methanol.
The nitrile solvent used in step (a) may preferably be selected from acetonitrile, propionitrile, butyronitrile or benzonitrile, and more preferable nitrile solvent is acetonitrile. The step (a) is preferably carried out at elevated temperature. The term "elevated temperature" refers to temperature at above 25°C. More preferably the step (a) is carried out at about 40 to 100°C and still more preferably at about 45 to 90°C.
Isolation of highly pure cinacalcet hydrochloride may preferably be carried out by methods known such as filtration or centrifugation.
The purification process yields cinacalcet hydrochloride with reduced levels of impurities, specifically, 2- [3 -(trifluoromethyl)phenyl]-5 - [3 -(trifluoromethyl)phenyl] -3 - hydroxy pentanal and (R)-l-(naphthyl)ethylamine.
The purity of cinacalcet hydrochloride is measured by High performance liquid chromatography (HPLC).
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 :
Preparation of 3-[3-(trifluoromethyI)phenyl]propionic acid
Palladium carbon (10%, 6 gm) was added to water (20 ml) and then added 3- (trifluoromethyl)cinnamic acid (100 gm) and toluene (1000 ml). The resulting contents were hydrogenated with hydrogen gas at a pressure of 4 kg at 45 to 50°C for 2 hour 30 minutes. The reaction mass was then filtered through celite bed and the layers were separated. The organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 98.7 gm of 3-[3-(trifluoromethyl)phenyl]propionic acid.
Example-2:
Preparation of methyl 3-[3-(trifluoromethyl)phenyl]propanoate
3-[3-(Trifluoromethyl)phenyl]propionic acid (100 gm) as obtained in example 1 was dissolved in methanol (250 ml) and then added concentrated sulfuric acid (45 gm) slowly for 25 minutes. The temperature of the reaction mass was raised to 40 to 45°C and maintained for 1 hour at 30 to 45°C. The methanol solvent was distilled off under vacuum at below 45°C to obtain residual mass. To the residual mass was added water (600 ml) and methylene dichloride (500 ml). The separated organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain 99.2 gm of methyl 3-[3-(trifluoromethyl)phenyl]propanoate.
Example-3 :
Preparation of 3-[3-(trifluoromethyl)phenyl]propionaIdehyde
Methyl 3-[3-(trifluoromethyl)phenyl]propanoate (5 gm) as obtained in example 2 was added to toluene (50 ml) and then cooled to -75 to -80°C. To the solution was added a solution of diisobutylaluminium hydride (4.59 gm) in n-hexane (33 ml) slowly for 1 hour 30 minutes at -75 to -80°C. The reaction mass was maintained for 1 hour at -75 to - 80°C and then added methanol (5 ml) at -75 to -80°C. The temperature of the reaction mass was raised to 0°C and the reaction mass was poured to the chilled water (150 ml). To the reaction mass was added ethyl acetate (50 ml) and then added sodium sulfate solution (20%, 25 ml). The reaction mass was maintained for 1 hour 30 minutes at room temperature and then filtered through celite bed. The layers were separated and the aqueous layer was extracted with toluene. The combined organic layer was dried over sodium sulfate and the solvent was. distilled off under reduced pressure to obtain 4.2 gm of 3-[3-(trifluoromethyl)phenyl]propionaldehyde.
3 - [3 -(Trifluoromethyl)phenyl]propionaldehyde : 99.2%;
3-[3-(Trifluoromethyl)phenyl]propanol impurity: 0.3%.
Example 4:
Preparation of cinacalcet hydrochloride
3-[3-(Trifluoromethyl)phenyl]propionaldehyde (14.2 gm) as obtained in example 3 was dissolved in tetrahydrofuran (50 ml) and then cooled to -45 to -50°C. To the solution was added a solution of (R)-(l-naphthyl)ethylamine (10 gm) in tetrahydrofuran (150 ml) at -45 to -50°C slowly for 2 hours 30 minutes and then added titanium(IV)isopropoxide (4.1 gm). The reaction mass was stirred for 15 minutes at -45 to -50°C and then added a solution of sodium cyanoborohydride (4 gm) in methanol (40 ml) slowly for 20 minutes. The temperature of the reaction mass was raised to room temperature and maintained for 2 hours at room temperature. To the reaction mass was added water (50 ml) and the reaction mass was then filtered through celite bed. The layers were separated and the aqueous layer was extracted with diisopropyl ether. The combined organic layer was dried and the solvent was distilled off under reduced pressure to obtain residual mass. To the residual mass was added diisopropyl ether (80 ml) and water (100 ml), and then heated to 55 to 60°C. Hydrochloride in diisopropyl ether (16% HCl, 12.5 ml) was added to the reaction mass at 55 to 60°C and maintained for 30 minutes at 55 to 60°C. The reaction mass was cooled to room temperature and maintained for 15 hours at room temperature. The separated solid was filtered and dried to obtain 18 gm of cinacalcet hydrochloride.
Cinacalcet hydrochloride: 98.5%;
2- [3 -(Trifluoromethyl)phenyl] -5 - [3 -(trifluoromethyl)phenyl] -3 -hydroxy pentanal impurity: 1.08%;
(R)-l-(Naphthyl)ethylamine impurity: 0.32%.
Example 5:
Preparation of cinacalcet hydrochloride
3-[3-(Trifluoromethyl)phenyl]propionaldehyde (7.07 gm) was dissolved in tetrahydrofuran (25 ml) and then cooled to -45 to -50°C. To the solution was added a solution of (R)-(l-naphthyl)ethylamine (5 gm) in tetrahydrofuran (75 ml) at -45 to -50°C slowly for 2 hours 30 minutes and then added titanium(IV)isopropoxide (2.07 gm). The reaction mass was stirred for 20 minutes at -45 to -50°C and then added a solution of sodium cyanoborohydride (2 gm) in methanol (20 ml) slowly for 20 minutes. The temperature of the reaction mass was raised to room temperature and maintained for 2 hours at room temperature. To the reaction mass was added water (25 ml) and the reaction mass was then filtered through celite bed. The layers were separated and the aqueous layer was extracted with diisopropyl ether. The combined organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure to obtain residual mass. To the residual mass was added diisopropyl ether (40 ml) and water (50 ml). The contents were heated to 55 to 60°C. Hydrochloride in ethyl acetate (16% HCl, 6.2 ml) was added to the reaction mass at 55 to 60°C and maintained for 30 minutes at 55 to 60°C. The reaction mass was cooled to room temperature and maintained for 15 hours at room temperature, filtered. The solid obtained was dried to obtain 9.5 gm of cinacalcet hydrochloride.
Cinacalcet hydrochloride: 98.6%; 2- [3 -(Trifluoromethyl)phenyl] -5- [3 -(trifluoromethyl)phenyl] -3 -hydroxy pentanal impurity: 1.05%;
(R)-l-(Naphthyl)ethylamine impurity: 0.3%.
Example 6:
Preparation of cinacalcet hydrochloride
3-[3-(Trifluoromethyl)phenyl]propionaldehyde (142 gm) was dissolved in diisopropyl ether (500 ml) and then cooled to -45 to -50°C. To the solution was added a solution of (R)-(l-naphthyl)ethylamine (100 gm) in diisopropyl ether (1400 ml) at -45 to -50°C slowly for 2 hours 30 minutes and then added titanium(IV)isopropoxide (41 gm). The reaction mass was stirred for 15 minutes at -45 to -50°C and then added a solution of sodium cyanoborohydride (40 gm) in methanol (380 ml) slowly for 20 minutes. The temperature of the reaction mass was raised to room temperature and maintained for 2 hours at room temperature. To the reaction mass was added water (450 ml) and the reaction mass was then filtered through celite bed. The layers were separated and the aqueous layer was extracted with diisopropyl ether. The combined organic layer was dried and the solvent was distilled off under reduced pressure to obtain residual mass. To the residual mass was added diisopropyl ether (700 ml) and water (1000 ml). The contents were heated to 55 to 60°C. Hydrochloride in diisopropyl ether (16% HC1, 125 ml) was added to the reaction mass at 55 to 60°C and maintained for 30 minutes at 55 to 60°C. The reaction mass was cooled to room temperature and maintained for 15 hours at room temperature, filtered. The solid was dried to obtain 175 gm of cinacalcet hydrochloride.
Cinacalcet hydrochloride: 98.5%;
2- [3 -(Trifluoromethyl)phenyl] -5- [3 -(trifluoromethyl)phenyl] -3 -hydroxy pentanal impurity: 1.08%;
(R)-l -(Naphthyl)ethylamine impurity: 0.32%.
Example 7:
Purification of cinacalcet hydrochloride
Cinacalcet hydrochloride (10 gm) as obtained in example 4 was dissolved in a mixture of water (125 ml) and methanol (15 ml). The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried at 60 to 65°C for 6 hours to obtain 9.2 gm of substantially pure cinacalcet hydrochloride.
Cinacalcet hydrochloride: 99.96%;
2- [3 -(Trifluoromethyl)phenyl] -5-[3 -(trifluoromethyl)phenyl] -3 -hydroxy pentanal impurity: Not detected;
(R)- 1 -(Naphthyl)ethylamine impurity: Not detected.
Example 8:
Purification of cinacalcet hydrochloride
Cinacalcet hydrochloride (10 gm) was suspended in a mixture of water (80 ml) and acetonitrile (20 ml). The contents were heated to 80°C and stirred for 20 minutes at
80°C to obtain solution. The solution was cooled to at room temperature and maintained for 2 hours. The separated solid was filtered and dried to obtain 8.3 gm of substantially pure cinacalcet hydrochloride.
Cinacalcet hydrochloride: 99.6%;
2-[3-(Trifluoromethyl)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-hydroxy pentanal impurity: Not detected;
(R)-l -(Naphthyl)ethylamine impurity: 0.11%.
Example 9:
Purification of cinacalcet hydrochloride
Cinacalcet hydrochloride (10 gm) was dissolved in methanol (15 ml). To the solution was added water (125 ml) slowly for 40 minutes to form precipitation. The reaction mass was stirred for 2 hour at room temperature and filtered. The solid obtained was dried to obtain 9.3 gm of substantially pure cinacalcet hydrochloride.
Cinacalcet hydrochloride: 99.98%;
2- [3 -(Trifluoromethyl)phenyl] -5- [3 -(trifluoromethyl)phenyl] -3 -hydroxy pentanal impurity: Not detected;
(R)- 1 -(Naphthyl)ethylamine impurity: Not detected.

Claims

claim:
1. A process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde of formula I,
Figure imgf000017_0001
which comprises, reducing the methyl 3-[3-(trifluoromethyl)phenyl]propanoate of formula II
Figure imgf000017_0002
wherein R' is lower alkyl.
with diisobutylaluminium hydride (DIBAL-H) in an hydrocarbon solvent, an chlorinated solvent, an ether solvent or mixtures thereof below -40°C to obtain a compound of formula I.
2. The process according to claim 1, wherein the R' is methyl or ethyl.
3. The process according to claim 2, wherein the R' is methyl.
4. The process according to claim 1 , wherein the solvent used in the process is selected from the group consisting of cyclohexane, cyclohexene, cycloheptane, cyclopentane, n-hexane, n-heptane, benzene, toluene, xylene, dichloromethane, chloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert- butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxy ethane.
5. The process according to claim 4, wherein the solvents are n-hexane, cyclohexane, toluene, dichloromethane, diisopropyl ether and tetrahydrofuran.
6. The process according to claim 5, wherein the solvents are n-hexane, toluene, dichloromethane and tetrahydrofuran.
7. The process according to claim 1, wherein the reaction mass is maintained in the process below -50°C.
8. The process according to claim 7, wherein the reaction mass is maintained at about -70 to -85°C.
9. A process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde, which comprises:
a. reducing the methyl 3-[3-(trifluoromethyl)phenyl]propanoate with diisobutylaluminium hydride (DIBAL-H) in an hydrocarbon solvent, an chlorinated solvent, an ether solvent or mixtures thereof below -40°C;
b. quenching the reaction mass with an alcohol solvent;
c. adding ethyl acetate to the reaction mass obtained in step (b);
d. separating out the solids; and
e. isolating 3-[3-(trifluoromethyl)phenyl]propionaldehyde from the mother liquor.
10. The process according to claim 9, wherein the suitable solvent used in step (a) is selected from the group consisting of cyclohexane, cyclohexene, cycloheptane, cyclopentane, n-hexane, n-heptane, benzene, toluene, xylene, dichloromethane, chloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxy ethane.
1 1. The process according to claim 10, wherein the solvents are n-hexane, cyclohexane, toluene, dichloromethane, diisopropyl ether and tetrahydrofuran.
12. The process according to claim 1 1, wherein the solvents are n-hexane, toluene, dichloromethane and tetrahydrofuran.
13. The process according to claim 9, wherein the reaction mass is maintained in step (a) below -50°C.
14. The process according to claim 13, wherein the reaction mass is maintained at about -70 to -85°C.
15. The process according to claim 9, wherein the alcohol solvent used in step (b) is a solvent or mixture of solvents selected from methanol, ethanol, isopropyl alcohol, isobutanol and n-butanol.
16. The process according to claim 15, wherein the alcohol solvent is methanol.
17. A process for the preparation of cinacalcet hydrochloride in high yields, which comprises:
a. adding 3-[3-(trifluoromethyl)phenyl]propionaldehyde to (R)-(l- naphthyl)ethylamine in ether solvent in the presence of titanium(IV)isopropoxide . below -5°C;
b. reacting sodium cyanoborohydride with the reaction mass obtained in step (a); c. concentrating the reaction mass;
d. adding ether solvent, hydrochloride in an organic solvent and water to the residual mass obtained in step (c); and
e. isolating cinacalcet hydrochloride.
18. The process according to claim 17, wherein the ether solvent used in step (a) and step (d) is independently a solvent or mixture of solvents selected from tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane and methoxy ethane.
19. The process according to claim 18, wherein the ether solvents are tetrahydrofuran and diisopropyl ether.
20. The process according to claim 17, wherein the reaction in step (a) is carried out below -20°C.
21. The process according to claim 20, wherein the reaction is carried out at about -30 to -60°C.
22. The process according to claim 17, wherein the organic solvent used in step (d) is a solvent or mixture of solvents selected from the group consisting of an ether solvent and an ester solvent.
23. The process according to claim 22, wherein the ether solvent is selected from tetrahydrofuran, diisopropyl ether, tertrahydropyran, 1 ,4-dioxane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, diglyme, dimethoxyethane, dimethoxymethane or methoxy ethane.
24. The process according to claim 22, wherein the ester solvents is selected ethyl acetate, methyl acetate, isopropyl acetate, tert-biityl methyl acetate or ethyl formate.
25. The process according to claim 23 and 24, wherein the organic solvents are diisopropyl ether and ethyl acetate.
26. The process according to claim 25, wherein the organic solvent is ethyl acetate.
27. A process for the purification of cinacalcet hydrochloride, which comprises:
a. stirring cinacalcet hydrochloride with a solvent system comprising water and solvent selected from alcohol solvent, nitrile solvent and mixture thereof; and b. isolating substantially pure cinacalcet hydrochloride.
28. The process according to claim 27, wherein the alcohol solvent used in step (a) is selected from methanol, ethanol, isopropyl alcohol, isobutanol or n-butanol.
29. The process according to claim 28, wherein the alcohol solvent is methanol.
30. The process according to claim 27, wherein the nitrile solvent used in step (a) is selected from acetonitrile, propionitrile, butyronitrile or benzonitrile.
31. The process according to claim 30, wherein the nitrile solvent is acetonitrile.
32. The process according to claim 27, wherein the step (a) is carried out at elevated temperature.
33. The process according to claim 32, wherein the step (a) is carried out at above 25°C.
34. The process according to claim 33, wherein the step (a) is carried out at about 40 to 100°C.
35. The process according to claim 34, wherein the step (a) is carried out at about 45 to 90°C.
PCT/IN2010/000477 2010-07-16 2010-07-16 Process for cinacalcet hydrochloride WO2012007954A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/IN2010/000477 WO2012007954A1 (en) 2010-07-16 2010-07-16 Process for cinacalcet hydrochloride
EP10854669.8A EP2593422B1 (en) 2010-07-16 2010-07-16 Process for cinacalcet hydrochloride
US13/810,319 US8921606B2 (en) 2010-07-16 2010-07-16 Process for cinacalcet hydrochloride

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2010/000477 WO2012007954A1 (en) 2010-07-16 2010-07-16 Process for cinacalcet hydrochloride

Publications (1)

Publication Number Publication Date
WO2012007954A1 true WO2012007954A1 (en) 2012-01-19

Family

ID=45469006

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2010/000477 WO2012007954A1 (en) 2010-07-16 2010-07-16 Process for cinacalcet hydrochloride

Country Status (3)

Country Link
US (1) US8921606B2 (en)
EP (1) EP2593422B1 (en)
WO (1) WO2012007954A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014020574A2 (en) * 2012-08-02 2014-02-06 Shasun Pharmaceuticals Limited Improved process for the preparation of calcimimetics

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6211244B1 (en) * 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US20070043243A1 (en) * 2005-05-16 2007-02-22 Revital Lifshitz-Liron Process for preparing Cinacalcet hydrochloride
WO2007127445A2 (en) 2006-04-27 2007-11-08 Teva Pharmaceutical Industries Ltd. Process for the preparation of cinacalcet base
WO2008035212A2 (en) 2006-06-08 2008-03-27 Medichem, S.A. Processes for preparing intermediate compounds useful for the preparation of cinacalcet
WO2008035381A2 (en) 2006-09-22 2008-03-27 Ind-Swift Laboratories Limited Process for the preparation of amine derivatives as calcimimetics
WO2008058235A2 (en) 2006-11-08 2008-05-15 Dr. Reddy's Laboratories, Ltd. Processes for the preparation of cinacalcet
WO2008068625A2 (en) 2006-06-08 2008-06-12 Medichem, S.A. Processes for preparing cinacalcet hydrochloride and polymorphic forms thereof
WO2008117299A1 (en) 2007-03-26 2008-10-02 Macleods Pharmaceuticals Limited Process for preparing cinacalcet hydrochloride
EP1990333A1 (en) * 2007-05-11 2008-11-12 Sandoz AG Process for the preparation of cinacalcet hydrochloride
WO2009128523A1 (en) 2008-04-17 2009-10-22 味の素株式会社 Immunostimulating agent
WO2009153814A1 (en) 2008-06-18 2009-12-23 Erregierre S.P.A. A process for the synthesis of cinacalcet hydrochloride
US20100174119A1 (en) * 2007-06-29 2010-07-08 Laurent Ducry Process for the preparation of aldehydes
WO2010103531A2 (en) 2009-03-09 2010-09-16 Megafine Pharma (P) Ltd. A new method for the preparation of cinacalcet and new intermediates thereof

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6211244B1 (en) * 1994-10-21 2001-04-03 Nps Pharmaceuticals, Inc. Calcium receptor-active compounds
US20070043243A1 (en) * 2005-05-16 2007-02-22 Revital Lifshitz-Liron Process for preparing Cinacalcet hydrochloride
WO2007127445A2 (en) 2006-04-27 2007-11-08 Teva Pharmaceutical Industries Ltd. Process for the preparation of cinacalcet base
WO2008068625A2 (en) 2006-06-08 2008-06-12 Medichem, S.A. Processes for preparing cinacalcet hydrochloride and polymorphic forms thereof
WO2008035212A2 (en) 2006-06-08 2008-03-27 Medichem, S.A. Processes for preparing intermediate compounds useful for the preparation of cinacalcet
WO2008035381A2 (en) 2006-09-22 2008-03-27 Ind-Swift Laboratories Limited Process for the preparation of amine derivatives as calcimimetics
WO2008058235A2 (en) 2006-11-08 2008-05-15 Dr. Reddy's Laboratories, Ltd. Processes for the preparation of cinacalcet
WO2008117299A1 (en) 2007-03-26 2008-10-02 Macleods Pharmaceuticals Limited Process for preparing cinacalcet hydrochloride
EP1990333A1 (en) * 2007-05-11 2008-11-12 Sandoz AG Process for the preparation of cinacalcet hydrochloride
US20100174119A1 (en) * 2007-06-29 2010-07-08 Laurent Ducry Process for the preparation of aldehydes
WO2009128523A1 (en) 2008-04-17 2009-10-22 味の素株式会社 Immunostimulating agent
WO2009153814A1 (en) 2008-06-18 2009-12-23 Erregierre S.P.A. A process for the synthesis of cinacalcet hydrochloride
WO2010103531A2 (en) 2009-03-09 2010-09-16 Megafine Pharma (P) Ltd. A new method for the preparation of cinacalcet and new intermediates thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
LEDNICER D. ET AL.: "Synthesis and antifertility activity of 4-and 5-(omega-arylalkyl) oxazolidinethiones.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 11, 1968, pages 1258 - 1262, XP055073193 *
SOBRERA ET AL., DRUGS FUTURE, vol. 27, no. 9, 2002
SYNTHETIC COMMUNICATIONS, vol. 38, no. 10, 2008, pages 1512 - 1517
TETRAHEDRON LETTERS, vol. 49, no. 1, 2008, pages 13 - 15
WANG ET AL.: "Synthesis of Cinacalcet congeners", TETRAHEDRON LETTERS, vol. 45, no. 45, 1 November 2004 (2004-11-01), pages 8355 - 8358, XP027280398 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014020574A2 (en) * 2012-08-02 2014-02-06 Shasun Pharmaceuticals Limited Improved process for the preparation of calcimimetics
WO2014020574A3 (en) * 2012-08-02 2014-03-27 Shasun Pharmaceuticals Limited Improved process for the preparation of calcimimetics

Also Published As

Publication number Publication date
EP2593422B1 (en) 2020-01-15
US20130178654A1 (en) 2013-07-11
EP2593422A4 (en) 2014-03-19
US8921606B2 (en) 2014-12-30
EP2593422A1 (en) 2013-05-22

Similar Documents

Publication Publication Date Title
EP1915335B1 (en) Process for the preparation of cinacalcet base
EP1881954B1 (en) Process for preparing cinacalcet hydrochloride
US7393967B2 (en) Process for the preparation of cinacalcet base
EP2403823B1 (en) Process for the preparation of cinacalcet and salts thereof, and intermediates for use in the process
WO2008058236A2 (en) Methods for preparing cinacalcet hydrochloride
WO2008117299A1 (en) Process for preparing cinacalcet hydrochloride
WO2010049293A2 (en) Process for preparing cinacalcet
US6232500B1 (en) Process for preparing a ketimine
EP2593422B1 (en) Process for cinacalcet hydrochloride
EP2477959A1 (en) Processes for the preparation of cinacalcet
US20070112074A1 (en) Tramadol recovery process
WO2014037563A1 (en) Process for preparing cinacalcet and pharmaceutically acceptable salts thereof
WO2010128388A2 (en) An improved process for the preparation of intermediate compounds useful for the preparation of cinacalcet
WO2003099761A1 (en) Process for the manufacture of sertraline
CZ2011770A3 (en) Process for preparing cinacalcet
WO2014020574A2 (en) Improved process for the preparation of calcimimetics
KR20130071389A (en) New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid
MXPA00006986A (en) Novel process for preparing a ketimine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10854669

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010854669

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 13810319

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE