Mehta Api Pvt Ltd, Cinacalcet hydrochloride, New patent, WO 2016027211

Mehta Api had cinacalcet hydrochloride under development and holds US DMF and European DMF as listed on the company’s website. Amgen and Kyowa Hakko Kirin, under license from NPS Pharmaceuticals, have developed and launched cinacalcet.

The present filing represents the first PCT filing from the assignee, which focuses on developing (using green chemistry) manufacturing and marketing of API’s- multi step, highly complex, potent, chiral and semi-synthetic, advance intermediates, specialty chemicals and building blocks.

PROCESS FOR THE PREPARATION OF CINACALCET AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

MEHTA API PVT. LTD. [IN/IN]; 203, Centre Point, 2nd Floor, Near Hotel Kohinoor, J.B. Nagar, Andheri-Kurla Road, Andheri (East), Maharashtra, Mumbai 400 059 (IN)

KHAN, Rao, Uwais, Ahmad; (IN).
PATHAK, Rajesh, Harshnath; (IN).
PATIL, Chetan, Vinesh; (IN).
GAIKWAD, Sanjay, Ramrao; (IN).
APAR, Shrikrishna, Motiram; (IN).
LINGE, Govind, Udhavrao; (IN).
SHAIKH, Mohammad, Umar; (IN)

Cinacalcet (N-[l-(R)-(-)-(l-naphthyl) ethyl]-3-[3-(trifluoromethyl) phenyl]-l-aminopropane) of Formula II, belongs to a category of calcimimetics class of compounds. It is useful for the treatment of hyperparathyroidism and the preservation of bone density in patients with kidney failure or hypercalcemia due to cancer. It is marketed under the trade name of Senipar in United States and under the trade name of Mimpara in Europe.

US6211244 and Drugs of the future (2002) 27 (9): 831, discloses a synthesis of Cinacalcet by reductive amination which implies the reaction of (R)-(l-naphthyl) ethylamine of formula (IV) with 3 -[3- (trifluoromethyl) phenyl] propionaldehyde of formula (V) in the presence of titaniumisopropoxide to afford the corresponding cinacalcet imine of formula (III), which is reduced to cinacalcet of formula (II) with NaBH₄CN in ethanol.

WO2012007954 A 1 discloses process for Cinacalcet by reductive amination in presence of titanium Isopropoxide using NaBH₄CN, wherein an ether solvent is used instead of ethanol. Indian patent applications 2268/DEL/2008 and 87/MUM/2011 disclose preparation of Cinacalcet wherein reaction of (R)-(I-naphthyl)ethylamine of formula (IV) with 3-[3-(trifluoromethyl)phenyl] propionaldehyde of formula (V) is carried out in the presence of titaniumisopropoxide to afford the corresponding cinacalcet imine, which is further reduced to cinacalcet with NaBH_4.

The above disclosed processes require the use of reagents such as NaBH₄CN, titanium isopropoxide, which are extremely toxic and flammable as well as not being environmentally sound. These reagents therefore make the industrial application of the process difficult.

US20110124917A1 and WO2008068625A2 both disclose preparation of Cinacalcet by reductive amination wherein reduction is performed by using sodiumtriacetoxyborohydride as a selective reducing agent for imines.

Sodiumtriacetoxyborohydride is hygroscopic in nature hence demands anhydrous conditions to be maintained rendering it not suitable for use on industrial scale.

WO2012007954 A 1 discloses reaction and work-up in THF followed by salt formation in Di-isopropyl ether and further purification in two solvent system consisting of Water and Methanol or Water and Acetonitrile. US20110124917 discloses reaction in Methanol, Workup in toluene, Salt formation in Ethyl Acetate and purification in Isopropanol. WO2008068625A2 discloses reaction, salt formation and Purification in two solvent system consisting of isobutyl Acetate and n-Heptane. 2268/DEL/2008 discloses reaction in MDC, Salt formation in Ethyl Acetate and Purification in Ethyl Acetate and Di-isopropyl ether. 87/MUM/2011 discloses reaction in THF, work-up in toluene. Salt formation in two solvent system consisting of cyclohexane and MTBE.

All the above prior-art process employs use of different solvents for each unit operation or a two-solvent system for purification, thereby rendering the processes not easily scalable on industrial scale.

1367/MUM/2009 discloses reductive amination using sodium borohydride with 67.6% yield reported. 3068/MUM/2012 discloses reductive amination using sodium borohydride with 86% yield but with less purity. Further 3068/MUM/2012 requires the usage of sulphuric acid for the reaction of (R)-(I-naphthyl)ethylamine of formula (II) with 3-[3-(trifluoromethyl)phenyl] propionaldehyde of formula (III).

Thus the processes disclosed above have one or other drawbacks, ranging from poor yield, purity, use of difficult to handle and toxic reagents or use of different solvents for each unit operation.

In view of the problems occurred in above methods, there remains a need for more economical and efficient industrially scalable process for the preparation of Cinacalcet and its pharmaceutically acceptable salts, which overcomes the drawbacks as disclosed in the prior art.

The present inventors have surprisingly found that when the condensation of [3-(trifluoromethyl)phenyl]propionaldehyde of formula – (V) with (R)-(l- naphthyl)ethylamine formula – (IV) is carried out in the absence of any reagent and water is removed under vacuum by azeotropic distillation at low temperatures in the optional presence of water scavengers, than Cinacalcet.hydrochloride with high purity and yield is obtained. Further the process is also industrially feasible due to the non-usage of hazardous reagents as also due to the reduction in isolation and purification steps.

Example I:

Preparation of Cinacalcet Hydrochloride, Formula (la)

To (1000 ml) toluene in a 4Neck Round Bottom flask along with dean-stark apparatus coupled to a condenser, charge (80gms) (R)-(l- naphthyl) ethylamine of formula – (IV). Cool to 10-15°C. Charge (lOOgms) 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V). Apply vacuum to the reaction mass through condenser and maintain for 8 hrs simultaneously azeotroping out water generated in the reaction till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. Release vacuum after the reaction complies. Water collected after Azeotropic distillation: 7-7.5 ml. Cool the reaction mass to 5-10°C. Charge (35 gms) sodium borohydride in two lots to the reaction mass and raise the temperature to 25-30°C. Maintain the reaction mass for 8 hrs to give Cinacalcet of formula (II) in-situ. After the reaction complies by thin layer chromatography adjust the pH of the reaction mass to about pH 6 using acetic acid. Charge (200 ml) water to the reaction mass and stir for 30 mins. Separate Layers the organic layer and treat with 15% HC1 (150 ml). Stirr the Reaction mass at 40 – 50°C for one hour and separate the layer. Heat the toluene at same temperature. Adjust pH of toluene layer to below pH-2 by treating with 15% HC1 (150 ml) at 40-45 °C. Distill out 500 ml toluene under vacuum below 45 °C. Gradually charge 500 ml water to the reaction mass along with simultaneously distilling out 500 ml toluene approximately. Filter the reaction mass to give crude Cinacalcet Hydrochloride. Dry at 45-50°C for 8 hrs.

Weight: 182 gms

% Yield on theoretical basis: 98.9%

Purity: 97.54%

To (182 gms) of Crude cinacalcet Hydrochloride charge (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Cool gradually at 25-30°C and further chill the reaction mass to 0°C -5°C. Maintain the reaction mass at 0-5°C for 2 hrs and filter under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether.

Wet cake is dried under vacuum at 40°C.

Weight: 163 gms

Yield on theoretical basis: 88.58%

Purity: 99.54%

To (163 gms) of MTBE pure Cinacalcet Hydrochloride is charged (400 ml) Isopropanol and heated to 70-75°C to get a clear solution which is then gradually cooled to 25-30°C and further chilled to 0-5 °C. The reaction mass is maintained for 2 hrs at same temperature and filtered under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C.

Weight: 157 gms

Yield on theoretical basis: 85.32%

Purity: 99.91%

Example II:

Preparation of Crude Cinacalcet Hydrochloride, Formula (la)

To (1000 ml) toluene in a 4Neck Round Bottom flask, is charged (80gms) (R)-(l-naphthyl)ethylamine of formula (IV). Cooled to 10-15°C. Charged (lOOgms) 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V) slowly. Charged (1 gm) Calcium Chloride and maintained for 8 hrs till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. After the reaction complies, the reaction mass is cooled to 5-10°C. Charged (35 gms) sodium borohydride in two lots to the reaction mass and raised the temperature to 25-30°C.The reaction mass is maintained for 8 hrs to give Cinacalcet Free base of formula (II) in-situ. After the reaction complies by thin layer chromatography pH of the reaction mass is adjusted to about pH 6 using acetic acid. Charged (200 ml) water to the reaction mass and stirred for 30 mins. Layers separated and the organic layer is treated with 15% HC1 (150 ml). Reaction mass is stirred at 40 – 50°C for one hour and layer separated. Toluene layer is water washed at same temperature. pH of toluene layer adjusted to below pH-2 by treating with 15% HC1 (150 ml) at 40-45°C. Distill out 500 ml toluene under vacuum below 45 °C. Gradually charge 500 ml water to the reaction mass along with simultaneously distilling out 500 ml toluene approximately. Filter the reaction mass to give crude Cinacalcet Hydrochloride. Dry at 45-50°C for 8 hrs

Weight: 178 gms

Yield on theoretical basis: 96.73%

Purity: 94.88%

To (178 gms) of Crude cinacalcet Hydrochloride charged (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Allowed to cool gradually at 25-30°C and further chilled the reaction mass to 0-5°C. Maintained the reaction mass at 0-5°C for 2 hrs and filtered under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether. Wet cake is dried under vacuum at 40°C.

Weight: 159 gms,

% Yield on theoretical basis: 86.40%

Purity: 99.77%

To (159 gms) of MTBE pure Cinacalcet Hydrochloride is charged (400 ml) Isopropanol and heated to 70-75°C to get a clear solution. Gradually cool to 25-30°C and further chill to 0-5 °C. Maintain the reaction mass is for 2 hrs at same temperature and filte under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C. Weight: 150 gms

% Yield on theoretical basis: 81.51 %

Purity: 99.91 %

Example III:

Preparation of Cinacalcet Hydrochloride, Formula (la)

To (1000 ml) toluene in a 4Neck Round Bottom flask, charge (80gms) (R)-(l-naphthyl)ethylamine of formula (IV). Cool to 10-15°C. Charge (lOOgms) 3-[(3-Trifluoromethyl)phenyl] propionaldehyde of formula (V). Charge ( 1 gm) Molecular Sieves and maintain the reaction mass for 8 hrs till the reaction complies by thin layer chromatography to give Cinacalcet imine of formula (III) in-situ. After the reaction complies, cool the reaction mass to 5-10°C. Charge (35 gms) sodium borohydride in two lots to the reaction mass and raise the temperature to 25-30°C. Maintain the reaction mass for 8 hrs to give Cinacalcet of formula (II) in-situ. After the reaction complies by thin layer chromatography adjust the pH of the reaction mass to about pH 6 using acetic acid. Charge (200 ml) water to the reaction mass and stir for 30 mins. Separate the layers and treat organic layer with 15% HC1 (150 ml).Stirr Reaction mass is at 40 – 50°C for one hour and separate layers. Water wash toluene layer at same temperature. Adjust pH of toluene layer pH-2 by treating with 15% HC1 (150 ml) at 40-45 °C. Distill and degasse under vacuum below 70°C to give Cinacalcet Hydrochloride

Weight: 172 gms

Yield on theoretical basis: 93.47%

Purity: 97.29%

To (172 gms) of Crude cinacalcet Hydrochloride charge (800 ml) Methyl tert butyl ether and stirr for 60°C for 3 hrs. Cool gradually at 25-30°C and further chill the reaction mass to 0-5 °C. Maintain the reaction mass at 0-5 °C for 2 hrs and filter under vacuum followed by washing to the wet-cake with (100 ml) chilled Methyl tert butyl ether.

Wet cake is dried under vacuum at 40°C.

Weight: 155 gms

% Yield on theoretical basis: 84.23%

Purity: 99.57%

To (155 gms) of MTBE pure Cinacalcet Hydrochloride charge (400 ml) Isopropanol and heat to 70-75°C to get a clear solution which is then gradually cooled to 25-30°C and further chill to 0-5 °C. Maintain the reaction mass i for 2 hrs at same temperature and filter under vacuum followed by washing with chilled isopropanol. Wet cake is dried under vacuum at 40°C.

Weight: 146 gms

% Yield on theoretical basis: 79.34%

Purity: 99.83%

 

Address: 203, Center Point, J.B. Next To Kohinoor,, J B Nagar, Andheri East, Mumbai, Maharashtra 400059

MR HARSHADRAI P MEHTA

Chairman & Managing Director

He is the founder of Mehta Group. With over five decades of dedicated work and a wealth of experience in the API Manufacturing field. He is the driving force behind MAPL’s success.

Devendra Mehta

Chief Executive Officer at MEHTA API PVT LTD

////////Mehta Api Pvt Ltd, Cinacalcet hydrochloride, New patent, WO-2016027211, WO 2016027211