Process for preparing cinacalcet hydrochloride   

The invention relates to a process for preparing the active product ingredient Cinacalcet hydrochloride (CNC.HCl), namely N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine hydrochloride of formula (I)

CNC.HCl, marketed as MIMPARA™ in the European Union, is a calcimimetic agent that decreases the secretion of parathyroid hormone by activating calcium receptors.

MIMPARA™ is approved for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease receiving dialysis and for the treatment of primary hyperparathyroidism (PHPT) in patients for whom parathyroidectomy is not clinically appropriate or contraindicated.

U.S. Pat. No. 6,011,068 discloses a class of arylalkylamines comprising generically Cinacalcet (CNC) and salts thereof. U.S. Pat. No. 6,211,244 describes specifically Cinacalcet or a pharmaceutically acceptable salt or complex thereof as the compound 22J, but it does not provide any specific examples for the preparation of Cinacalcet and/or Cinacalcet hydrochloride.

Most prior art processes for preparing the hydrochloride salt of Cinacalcet typically comprise: providing a solution of Cinacalcet in a solvent; treating said solution with an amount of hydrochloric acid sufficient to convert Cinacalcet to its hydrochloride salt; precipitating said hydrochloride salt and recovering said salt.

For example, U.S. Pat. No. 7,247,751 generically describes a method of preparing Cinacalcet hydrochloride crystalline form I, which comprises providing a solution of Cinacalcet base in a solvent in which Cinacalcet hydrochloride has a low solubility; acidifying the solution with hydrochloric acid to obtain a reaction mixture; maintaining the reaction mixture to obtain a precipitate; and recovering the precipitated Cinacalcet hydrochloride crystalline Form I. Preferably, the solvent is selected from the group consisting of acetone, ethanol, isopropyl alcohol, and methanol. The preparation of Cinacalcet hydrochloride crystalline form I from Cinacalcet is specifically described in Example 5 of U.S. Pat. No. 7,247,751, wherein a solution of Cinacalcet was formed by dissolving Cinacalcet base in absolute ethanol, hydrochloric acid was added drop-wise to the solution and the resulting mixture was stirred at ambient temperature, producing a precipitate. The product was isolated by filtration and dried in a vacuum, yielding Cinacalcet hydrochloride crystalline form I. Example 9 of WO 2008/058235 discloses the preparation of Cinacalcet hydrochloride starting from N-[(1R)-1-(1-napthyl)ethyl]-3-(3-trifluoromethyl)phenyl]propanamide, without isolating Cinacalcet free base.

WO 2008/058235 provides a process for making Cinacalcet hydrochloride from Cinacalcet that includes the steps of: providing a solution of Cinacalcet in an alcohol or alkyl acetate; treating the solution of the free base with an hydrochloric acid to convert the free base to the hydrochloride salt; adding an anti-solvent to solution containing the hydrochloride salt to precipitate it in the form of a solid; and isolating the precipitated solid to obtain the Cinacalcet hydrochloride. WO 2008/058235 also describes a process for making Cinacalcet hydrochloride by providing a solution of an acid addition salt of Cinacalcet other than Cinacalcet hydrochloride, treating said solution with an amount of hydrochloric acid sufficient to convert the acid addition salt to said hydrochloride salt; and isolating said cinacalcet hydrochloride.

U.S. Pat. No. 7,393,967 discloses a process for preparing Cinacalcet hydrochloride via coupling of 3-bromotrifluorotoluene with (R)—N-(1-(naphthalen-1-yl)ethyl)prop-2-en-1-amine in the presence of a catalyst and at least one base to obtain (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine (Example 1, Step 1), reducing the unsaturated Cinacalcet to obtain Cinacalcet (example 1, Step 2), and converting Cinacalcet to Cinacalcet hydrochloride (Example 2 or Example 3) as depicted in the following Scheme 1:

The present invention provides, in a first aspect, a novel and efficient method that leads to a Cinacalcet salt, especially the hydrochloride, which is convenient for the industrial scale and provides the desired product in good yields. In particular, the inventors found that Cinacalcet hydrochloride can be advantageously obtained with a process, which does not contemplate the isolation of Cinacalcet free base.

Accordingly, it is an object of the present invention to provide a method for preparing Cinacalcet hydrochloride of formula (I)

which comprises the steps of: e) reducing a compound of formula (VII)

wherein Z is chloride or another pharmaceutically acceptable anionic counterion, to obtain a compound of formula (Ia)

wherein Z is as defined above and, when in a compound of formula (Ia) Z is a pharmaceutically acceptable anionic counterion different from chloride, f) converting said compound of formula (Ia) to Cinacalcet hydrochloride of formula (I).

A “pharmaceutically acceptable anionic counterion” Z refers to a negatively charged molecule or atom that is balanced by the positively charged protonated Cinacalcet. A pharmaceutically acceptable anionic counterion may be organic or inorganic. For example, representative pharmaceutically acceptable anionic counterions include chloride, bromide, bisulfate (hydrogen sulfate), methanesulfonate, p-toluenesulfonate, phosphate, hydrogenphosphate, oxalate, formate, acetate, citrate, tartrate, succinate, maleate and malonate. Chloride, bisulfate, p-toluenesulfonate, tartrate and succinate are preferred; chloride and bisulfate are more preferred.

As an example, the compound of formula (VII) wherein Z is chloride is the compound of formula (VIIa),

the compound of formula (VII) wherein Z is bisulfate is the compound of formula (VIIb),

the compound of formula (VII) wherein Z is tartrate is the compound of formula (VIIc),

the compound of formula (VII) wherein Z is succinate is the compound of formula (VIId),

and the compound of formula (VII) wherein Z is p-toluenesulfonate is the compound of formula (VIIe)

In a preferred aspect, the present invention is directed to a method for preparing Cinacalcet hydrochloride of formula (I), which comprises the step of reducing the compound of formula (VIIa) as defined above.

In another aspect, the method according to the present invention further comprises obtaining the compound of formula (VIIa) as defined above, by a process which comprises the step of: g) converting a compound of formula (VII) wherein Z is a pharmaceutically acceptable anionic counterion different from chloride.

In a further preferred aspect, the method according to the present invention further comprises obtaining the compound of formula (VIIa) as defined above, by a process which comprises the step of:

g) converting a compound of formula (VIIb) as defined above.

The reduction according to the above step e) can be carried out starting from a compound of formula (VII), particularly the compound of formula (VIIa), by catalytic hydrogenation, i.e. with molecular hydrogen in the presence of a catalyst. The catalytic hydrogenation may be performed by any method known to a person skilled in the art. For example, a compound of formula (VII), particularly the compound of formula (VIIa), may be dissolved in a in a suitable solvent and exposed to H2 pressure, in the presence of a catalyst such as, for example, Pd/C, PtO2 (Adam\'s catalysts), Raney nickel or PdCl2. When the catalyst is selected from Pd/C, PtO2 or PdCl2, the H2 pressure is chosen in the range of from 0.5 to 5 atm, while when the catalyst is Raney nickel, the H2 pressure is chosen in a higher range from 4 to 70 atm. The suitable solvent can be selected from the group consisting of a C2-C5 nitrile such as, for example, acetonitrile; a linear or branched C1-C4 alcohol such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl alcohol; a linear or branched C3-C9 ketone such as, for example, methylethyl or methylisobutyl ketone; a linear or branched C3-C7 ester such as, for example, ethyl, iso-propyl or n-butyl acetate; toluene and mixtures thereof. Preferably, the solvent can be selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate and mixtures thereof, more preferably the solvent is methanol. Typically, the hydrogenation is carried out over a period of about 1 hour to 96 hours. Reaction temperature may range from 0° to 50° C., preferably from 10° to 30° C., more preferably at 20° C.

The conversion of a compound of formula (Ia) into Cinacalcet hydrochloride of formula (I) according to the above step f), and the conversion of a compound of a formula (VII) where Z is an anionic counterion different from chloride into a compound of formula (VIIa) according to step g), can be carried out dissolving a compound of formula (Ia) as defined above or, respectively, a compound (VII) as defined above, in a solvent selected from water; a linear or branched C1-C4 alcohol such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl alcohol; a linear or branched C4-C8 ester such as, for example, ethyl acetate, isopropyl acetate or n-butyl acetate; or mixtures thereof, at a temperature ranging from room temperature to the boiling point of the selected solvent, or mixture of solvents, and treating said compounds with aqueous hydrochloric acid. A moderately high excess of hydrochloric acid (2-10 equiv.) has to be used when the acid HZ is a stronger acid than hydrochloric acid.

The conversion of a compound of formula (VII) where Z is an anionic counterion different from chloride into a compound of formula (VIIa) according to step g), can be alternatively carried out suspending a compound of formula (VII) as defined above in a solvent selected from toluene; a linear or branched C4-C8 ether such as, for example, methyl tert-butyl ether, diisopropyl ether or di-n-butyl ether; a linear or branched C4-C8 ester such as, for example, ethyl acetate, isopropyl acetate or n-butyl acetate; or mixtures thereof, and treating said compound with an aqueous base, such as for example sodium hydroxide, sodium or potassium carbonate, sodium or potassium hydrogen carbonate, sodium or potassium phosphate, extracting the so obtained unsaturated Cinacalcet free base (CNC-ene free base) in the organic layer and precipitating the compound of formula (VIIa) from the organic solvent upon treatment with aqueous hydrochloric acid.

A compound of formula (VII) can be obtained converting (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine (CNC-ene free base) by any method known to a person skilled in the art. CNC-ene free base can be prepared, for example, as depicted in the U.S. Pat. No. 7,393,967, Example 1, Step 1, or following the teachings of the ZaCh System co-pending European patent application No. 08167762.7.

Alternatively, a compound of formula (VII), wherein Z is a pharmaceutically acceptable anionic counterion different from chloride, can be obtained with a novel method which comprises the step of:

j) eliminating sulfuric acid from the compound of formula (VIII)

wherein the wavy line represents a bond connected to carbon having R or S configuration, with a strong acid, neutralizing and acidifying with the proper acid HZ, wherein Z is a pharmaceutically acceptable anionic counterion different from chloride.

In a preferred aspect, the compound of formula (VIIb) as defined above can be obtained by a method which comprises the step of: j) eliminating sulfuric acid from the compound of formula (VIII) as defined above with a strong acid, neutralizing and acidifying with H2SO4.

It is therefore another object of the present invention to provide a method for preparing Cinacalcet hydrochloride of formula (I) as defined above, which further comprises preparing a compound of formula (VII) wherein Z is a pharmaceutically acceptable anionic counterion different from chloride, with a process which comprises the above step j).

The elimination of sulfuric acid according to the above step j) can be carried out by reacting the compound of formula (VIII) with a strong acid such as, for example, sulfuric or phosphoric acid, preferably concentrated sulfuric acid, with or without a solvent selected from high boiling toluene, n-butyl acetate and n-butyl ether, preferably n-butyl acetate, and at a temperature ranging from room temperature to the refluxing temperature of the selected solvent, preferably 115° C. Once the reaction has gone to completion, a compound (VII) wherein Z is a pharmaceutically acceptable anionic counterion different from chloride, can be obtained by any work up method known to a person skilled in the art. For example, a compound of formula (VII) as defined above can be isolated by neutralizing the acidic reaction mixture with an aqueous base, preferably sodium hydroxide, extracting the compound (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine (CNC-ene free base) in organic phase, preferably in n-butyl acetate, acidifying said organic phase with the proper acid HZ, wherein Z is a pharmaceutically acceptable anionic counterion different from chloride, preferably bisulfate, and precipitating the corresponding compound of formula (VII).

It is a further object of the present invention the Cinacalcet intermediate of formula (VIII) as defined above.

The compound of formula (VIII) as defined above can be obtained with a novel method which comprises the step of:

k) reducing the compound of formula (V)

to the corresponding benzylic alcohol of formula (Va)

in the presence of a reducing agent or by mean of a catalytic hydrogenation process, and l) converting the compound of formula (Va) into the sulfate ester of formula (VIII).

In the formula (Va), [ ] means that the compound of formula (Va) can be isolated or not from the reaction mixture.

The reduction of the compound of formula (V) according to the above step k) can be carried out with suitable reducing agents including sodium borohydride; lithium borohydride; diisobutyl aluminium hydride; and 1,1,3,3-tetramethyldisiloxane in combination with a Lewis acid. Suitable reduction catalysts, which can be used with gaseous hydrogen, include Pd/C, PtO2 (Adam\'s catalysts), Raney nickel and PdCl2. The reaction can be carried out in a solvent selected from, for example, water; a linear or branched C1-C4 alcohol such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl or sec-butyl alcohol; a linear or branched C4-C8 ether such as 1,2-dimethoxyethane, 2-methoxyethyl ether, diisopropyl ether, di-n-butyl ether, methyl tert-butyl ether, tetrahydrofuran or 1,4-dioxane; or a mixture thereof, depending on the reducing agent; at a temperature ranging between −10° to 40° C., over a period of about 0.5 to 10 hours. When the catalyst Pd/C, PtO2 or PdCl2 is used, the H2 pressure is typically 1 atm. When Raney nickel is used, the H2 pressure is moderately high (—1000 psi). Typically, the hydrogenation is carried out over a period of about 5 to about 24 hours. When the reduction is carried out upon catalytic transfer hydrogenation (CTH) conditions, suitable hydrogen-bearing feed materials such as, for example, formic acid, ammonium formate or sodium formate, preferably ammonium formate or sodium formate are employed. In order to activate the hydrogen-bearing material as hydrogen donor, a catalyst as defined above is employed: the catalyst promotes the hydrogen transfer from hydrogen-bearing feed material to the substrate. CTH may be performed by any method known to a person skilled in the art. In particular, when CTH techniques are used in the reaction under step k), the compound of formula (V) is dissolved in a solvent selected from for example, toluene, acetic acid and a C1-C5 alcohol as defined above, preferably ethyl alcohol, in the presence of formic acid, ammonium formate or sodium formate, preferably ammonium formate or sodium formate, at refluxing temperature of the selected solvent, over a period of about 5 to 48 hours. In a most preferred embodiment, sodium borohydride in methanol at a temperature ranging from −10° C. to 10° C. is used.

Once the intermediate benzylic alcohol of formula (Va) is formed, either it is isolated or not, it can be converted into the sulfate ester of formula (VIII) according to the above step 1) by treatment with sulfuric acid and acetic anhydride, in a solvent selected from acetonitrile, a C4-C8 ether as defined above, a linear or branched C4-C6 ester, such as, ethyl, iso-propyl, n-butyl acetate, or a mixture thereof, at a temperature ranging from 0°-50° C., most preferably at 25° C.

It is therefore another object of the present invention to provide a method for preparing Cinacalcet hydrochloride of formula (I) as defined above, which further comprises preparing the compound of formula (VIII), with a process which comprises the above steps k) and l), with or without the isolation of the intermediate compound of formula (Va).

For clarity\'s sake, the above processes may be illustrated by the following Scheme 2:

In a particular aspect, the present invention provides a method for preparing Cinacalcet hydrochloride of formula (I)

which comprises the steps of k) reducing the compound of formula (V)

to the corresponding benzylic alcohol of formula (Va)

wherein [ ] means that the compound of formula (Va) can be isolated or not from the reaction mixture, in the presence of a reducing agent or by mean of a catalytic hydrogenation process, l) converting the compound of formula (Va) into the sulphate ester of formula (VIII)

wherein the wavy line represents a bond connected to carbon having R or S configuration, j) eliminating sulfuric acid from the compound of formula (VIII) with a strong acid, neutralizing and acidifying with H2SO4 to give the compound of formula (VIIb)

g) converting the compound (VIIb) into the compound (VIIa) and

e) reducing the compound (VIIa) to obtain Cinacalcet hydrochloride of formula (I).

The compound of formula (V) as defined above can be prepared according to the methods described in ZaCh System\'s co-pending European patent application No. 08167762.7, which comprises the step of:

a) reacting 3-(trifluoromethyl)acetophenone of formula (II)

with (R)-(1-naphthyl)ethylamine of formula (III), optionally in the hydrochloride form,

in the presence of formaldehyde and hydrochloric acid to give the compound of formula (V)

In a preferred aspect of the present invention, the reaction under the above step a) is carried out with (R)-(1-naphthyl)ethylamine hydrochloride salt.

It is therefore a further object of the present invention to provide a method for preparing Cinacalcet hydrochloride of formula (I) as defined above, which further comprises preparing the compound of formula (V), with a process which comprises the above step a).

According to ZaCh System co-pending European patent application No. 08167762.7, the compound of formula (V) can also be prepared with a process which comprises the steps of:

b) reacting the compound of formula (II) as defined above (i) with a compound of formula

HNR1R2, wherein R1 and R2 represent, independently, hydrogen or C1-C5 alkyl, provided that when one of R1 and is hydrogen, the other is not hydrogen; or wherein R1 and R2 together form a C4-C7 alkyl bridge, so that with the inclusion of the nitrogen atom to which they are linked a heterocycle is formed, wherein one —CH2— group of the C4-C7 alkyl bridge, can be replaced by —O—, in the presence of formaldehyde; or (ii) with a N-methyl-N-methylenemethanaminium halide of formula

wherein Hal is a halogen atom, to obtain the compound of formula (IV)

wherein R1 and R2 are as defined above;

Download full PDF for full patent description/claims.




You can also Monitor Keywords and Search for tracking patents relating to this Process for preparing cinacalcet hydrochloride patent application.
###


Other recent patent applications listed under the agent Zach System S.p.a.: