Classifications

• • 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
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/28—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by unsaturated carbon chains
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
  • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C305/00—Esters of sulfuric acids
  • C07C305/02—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to acyclic carbon atoms of a carbon skeleton
  • C07C305/12—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to acyclic carbon atoms of a carbon skeleton being saturated and containing rings

Definitions

• 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 MIMPARATM in the European Union, is a calcimimetic agent that decreases the secretion of parathyroid hormone by activating calcium receptors.
• MIMPARATM 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.
• SHPT secondary hyperparathyroidism
• PHPT primary hyperparathyroidism
• U.S. Pat. No. 6,011,068 discloses a class of arylalkylamines comprising generically Cinacalcet (CNC) and salts thereof.
• CNC Cinacalcet
• 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.
• 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.
• the solvent is selected from the group consisting of acetone, ethanol, isopropyl alcohol, and methanol.
• 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.
• Cinacalcet hydrochloride can be advantageously obtained with a process, which does not contemplate the isolation of Cinacalcet free base.
• 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.
• 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.
• the compound of formula (VII) wherein Z is chloride is the compound of formula (VIIa),
• 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.
• 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:
• 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:
• 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.
• a compound of formula (VII), particularly the compound of formula (VIIa) may be dissolved in a in a suitable solvent and exposed to H 2 pressure, in the presence of a catalyst such as, for example, Pd/C, PtO 2 (Adam's catalysts), Raney nickel or PdCl 2 .
• the H 2 pressure is chosen in the range of from 0.5 to 5 atm, while when the catalyst is Raney nickel, the H 2 pressure is chosen in a higher range from 4 to 70 atm.
• the suitable solvent can be selected from the group consisting of a C 2 -C 5 nitrile such as, for example, acetonitrile; a linear or branched C 1 -C 4 alcohol such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl alcohol; a linear or branched C 3 -C 9 ketone such as, for example, methylethyl or methylisobutyl ketone; a linear or branched C 3 -C 7 ester such as, for example, ethyl, iso-propyl or n-butyl acetate; toluene and mixtures thereof.
• a C 2 -C 5 nitrile such as, for example, acetonitrile
• a linear or branched C 1 -C 4 alcohol such as, for example, methyl, ethyl,
• the solvent can be selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate and mixtures thereof, more preferably the solvent is methanol.
• 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 C 1 -C 4 alcohol such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl or tert-butyl alcohol; a linear or branched C 4 -C 8 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 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 C 4 -C 8 ether such as, for example, methyl tert-butyl ether, diisopropyl ether or di-n-butyl ether; a linear or branched C 4 -C 8 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
• 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.
• 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:
• the compound of formula (VIIb) as defined above can be obtained by a method which comprises the step of:
• 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.
• 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.
• 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).
• an aqueous base preferably sodium hydroxide
• 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, PtO 2 (Adam's catalysts), Raney nickel and PdCl 2 .
• the reaction can be carried out in a solvent selected from, for example, water; a linear or branched C 1 -C 4 alcohol such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl or sec-butyl alcohol; a linear or branched C 4 -C 8 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.
• a solvent selected from, for example, water; a linear or branched C 1 -C 4 alcohol such as, for example, methyl, ethyl, n-propyl,
• the H 2 pressure is typically 1 atm.
• the H 2 pressure is moderately high (—1000 psi).
• the hydrogenation is carried out over a period of about 5 to about 24 hours.
• suitable hydrogen-bearing feed materials such as, for example, formic acid, ammonium formate or sodium formate, preferably ammonium formate or sodium formate are employed.
• 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.
• the compound of formula (V) is dissolved in a solvent selected from for example, toluene, acetic acid and a C 1 -C 5 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.
• a solvent selected from for example, toluene, acetic acid and a C 1 -C 5 alcohol as defined above, preferably ethyl alcohol
• 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.
• sodium borohydride in methanol at a temperature ranging from ⁇ 10° C. to 10° C. is used.
• the intermediate benzylic alcohol of formula (Va) 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 C 4 -C 8 ether as defined above, a linear or branched C 4 -C 6 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.
• the present invention provides a method for preparing Cinacalcet hydrochloride of formula (I)
• reaction under the above step a) is carried out with (R)-(1-naphthyl)ethylamine hydrochloride salt.
• the compound of formula (V) can also be prepared with a process which comprises the steps of:
• the mass was diluted by addition of toluene (85.0 g) and, dropwise, water (50.0 g), then stirred at 25° C. for few minutes.
• the organic and aqueous phases were separated and the toluene layer was cooled to 5° C. and neutralized by addition of aqueous ammonia (28% w/w; 40.0 g) up to pH 10.
• aqueous ammonia (28% w/w; 40.0 g) up to pH 10.
• water 30.0 g was added in order to solubilise salts, the phases were separated and the solvent was removed form the organic layer via reduced pressure distillation.
• the crude title compound was obtained as a pale yellow oil (17.7 g).
• a 500 ml reactor is loaded with (R) and (S)-3-((R)-1-(naphthalen-1-yl)ethylammonio)-1-(3-(trifluoromethyl)phenyl)propyl sulfate (VIII) (55.0 g, 121.287 mmol) and n-butyl acetate (250 ml), and 96% H 2 SO 4 (37.1 g, 363.169 mmol, 3.0 equiv.) is added dropwise at room temperature. The reaction mixture is heated up to 115° C. and stirred for 15 hours, then cooled down to 15° C. The reaction mixture is washed with water (2 ⁇ 110 ml), 6% w/w aq.
• Cinacalcet hydrochloride (I) from (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine hydrochloride salt (VIIa)
• Cinacalcet bisulfate (1.0 g, 2.200 mmol) is dissolved in a hot water/2-propanol mixture (12-14 mL). The solution is then cooled down to 20° C. and concentrated hydrochloric acid (1.0 g, 8.493 mmol) is added. A white precipitate is formed, the slurry is filtered and the solid washed with water. Cinacalcet hydrochloride (I) (0.7 g, 1.777 mmol, 80.8% yield) is obtained as a white powder. (HPLC assay: 99.5% w/w).

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• 2010
  • 2010-02-16 AU AU2010215520A patent/AU2010215520B2/en active Active
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