WO2008035212A2 - Processes for preparing intermediate compounds useful for the preparation of cinacalcet - Google Patents

Processes for preparing intermediate compounds useful for the preparation of cinacalcet Download PDF

Info

Publication number
WO2008035212A2
WO2008035212A2 PCT/IB2007/003346 IB2007003346W WO2008035212A2 WO 2008035212 A2 WO2008035212 A2 WO 2008035212A2 IB 2007003346 W IB2007003346 W IB 2007003346W WO 2008035212 A2 WO2008035212 A2 WO 2008035212A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
approximately
sodium hypochlorite
cinacalcet
vii
Prior art date
Application number
PCT/IB2007/003346
Other languages
French (fr)
Other versions
WO2008035212A3 (en
Inventor
Tibor Szekeres
József RÉPÁSI
András Szabó
Bernardino Mangion
Original Assignee
Medichem, S.A.
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 Medichem, S.A. filed Critical Medichem, S.A.
Priority to US12/303,903 priority Critical patent/US20100267988A1/en
Priority to CA002659153A priority patent/CA2659153A1/en
Priority to JP2009513799A priority patent/JP2009539823A/en
Priority to EP07858859A priority patent/EP2041056A2/en
Publication of WO2008035212A2 publication Critical patent/WO2008035212A2/en
Publication of WO2008035212A3 publication Critical patent/WO2008035212A3/en
Priority to IL195757A priority patent/IL195757A0/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/32Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions without formation of -OH groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/18Drugs for disorders of the endocrine system of the parathyroid hormones
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/17Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrogenation of carbon-to-carbon double or triple bonds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/30Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00Compounds having —CHO groups
    • C07C47/20Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/24Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing halogen

Definitions

  • the invention relates, in general, to an improved process for preparing compounds ⁇ e.g., 3-(3-trifluoromethylphenyl)propanal (Compound III, below)), which are key intermediates for the synthesis of cinacalcet, its salts and/or solvates thereof, as well as the use of such compounds prepared by such process for the preparation of cinacalcet and/or its salts or solvates.
  • compounds ⁇ e.g., 3-(3-trifluoromethylphenyl)propanal (Compound III, below)
  • Compound III 3-(3-trifluoromethylphenyl)propanal
  • Cinacalcet is a commercially marketed pharmaceutically active substance known to be useful for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma.
  • Cinacalcet is the international commonly accepted name for N-[I -(RH")- 1-naphthy l)ethyl] 7 3-[3- (trifluoromethyl)phenyl]-l-aminopiOpane hydrochloride, which has an empirical formula of C 22 H 22 F 3 N ⁇ CI, a molecular weight of 393.9 and has the structural formula (I):
  • U.S. Patent No. 6,011,068 generally describes cinacalcet and its pharmaceutically acceptable acid addition salts, but does not provide any examples for the preparation of the same.
  • U.S. Patent No. 6,211,244 describes cinacalcet and its pharmaceutically acceptable acid chloride addition salt, but does not provide any examples for the preparation of cinacalcet and/or cinacalcet hydrochloride.
  • Drugs 2002, 27(9), 831-836 discloses a synthetic scheme for preparing cinacalcet hydrochloride according to the general procedure described in U.S. Patent No. 6,211,244. This disclosed synthetic route is illustrated in Scheme 1, below.
  • European Patent EP 0 194 764 discloses a process for preparing Compound III in which Compound IV ⁇ i.e., 3-trifluoromethyIbromobenzene) is reacted with Compound V ⁇ i.e., propargyl alcohol) using bis(triphenylphosphine)palladium chloride and cuprous iodide in triethylamine, followed by catalytic hydrogenation to give the corresponding alcohol (compound VII).
  • Compound VII is then converted to Compound III by a Swern oxidation. This synthetic procedure is illustrated in Scheme 2, below.
  • the invention relates, in general, to an improved process for preparing compounds (e.g., 3-(3-trifluoromethylphenyl)propanal (Compound HI)), which are key intermediates for the synthesis of cinacalcet, its salts and/or solvates thereof, as well as the use of such compounds prepared by such process for the preparation of cinacalcet and/or its salts or solvates.
  • compounds e.g., 3-(3-trifluoromethylphenyl)propanal (Compound HI)
  • the invention provides an improved process for preparing Compound III.
  • the process of the invention for preparing Compound HI and similar compounds obviates the need to employ a Swern oxidation step (as required in the above-described processes) and therefore avoids the need to employ low temperature oxidation reactions as well as the unpleasant odors associated with such procedures.
  • the process of the invention includes oxidation of Compound VIl with an oxidizing agent using a nitroxyl compound as catalyst in an inert solvent.
  • the invention further includes a process for preparing Compound VII from compound VI.
  • the invention further provides a process for preparing Compound VI (i.e., 3-(3- trifluoromethylphenyl)propynol) using lower amounts of catalyst and in which the catalyst can be at least partially recycled.
  • the processes of the invention are clean, fast, have high volume efficacy and require no chromatographic purifications. These characteristics of the processes of the invention make them very suitable for industrial scale up.
  • the invention relates, in general, to an improved process for preparing compounds (e.g., 3-(3-trifluoromethylphenyl)propanal (Compound HI)), which are key intermediates for the synthesis of cinacalcet, its salts and/or solvates thereof, as well as the use of the such compounds prepared such process for the preparation of cinacalcet and/or its salts or solvates.
  • the process of the invention includes oxidation of Compound VII with an oxidizing agent using a nitroxyl compound as catalyst in an inert solvent to yield Compound III.
  • a suitable nitroxyl compound for use in the invention includes TEMPO (2,2,6,6,-tetramethy-l-piperidinyloxy free radical).
  • a suitable oxidation agent for use in the invention includes sodium hypochlorite.
  • Suitable inert solvents for use in the invention include any solvent that does not take part in the reaction.
  • Preferred inert solvents include, for example, cyclic or acyclic alkanes (e.g., hexane, heptane, methylcyclohexane), aromatic solvents (e.g., toluene), halogenated solvents (e.g., dichloromethane, dichloroethane, chloroform), esters (e.g., ethyl acetate, butyl acetate, isopropyl acetate) or ethers (e.g., diethyl ether, tetrahydrofuran or tert-butyl methyl ether) and/or mixtures thereof.
  • cyclic or acyclic alkanes e.g., hexane, heptane, methyl
  • the oxidation reaction is performed using between approximately 0.9 to approximately 2.0 moles of sodium hypochlorite per mol of Compound VII, preferably approximately 1.05 moles. It was furthermore found to be advantageous to add the sodium hypochlorite in portions to the reaction mixture. Preferably, approximately 1 mole of sodium hypochlorite per mol of Compound VII was added to the reaction mixture in a first portion, and after a period of stirring, a second portion of approximately 0.05 moles of sodium hypochlorite per mol of Compound VII was added.
  • the reaction can optionally be performed using potassium bromide as a regenerating agent of the nitroxyl compound used as catalyst.
  • the oxidation reaction is conducted using a range of temperatures of approximately 5° C to approximately 25° C and for a time of approximately 10 to approximately 60 minutes. More preferably below 15 0 C, and for a time of approximately 20 to approximately 60 minutes.
  • Compound III can be treated with sodium bisulphite to obtain a bisulphite adduct that can be further converted to a purified Compound III.
  • Compound III can be purified by distillation under vacuum.
  • Compound VII can be obtained according to the process described in the European Patent EP 0 194 764 (see Scheme 2, above).
  • the reaction of Compound IV with Compound V can be performed using 10% Pd/C catalyst, triphenyl phosphine, copper (I) iodide and diisopropylamine, to yield Compound VT.
  • Compound VI can readily be converted to Compound V ⁇ via catalytic hydrogenation in the presence of Pd/C catalyst
  • Another aspect of the invention includes the use of Compound III obtained according to the above-described processes for producing cinacalcet and/or its pharmaceutically acceptable salts and/or solvates thereof.
  • Compound III obtained according to the above-described processes for producing cinacalcet and/or its pharmaceutically acceptable salts and/or solvates thereof.
  • the gas chromatographic separation was carried out using a RTX-50, 30m x 0.32 mm x 0.25 ⁇ m column, a head pressure of 10 psi and helium as the carrier gas. Temperature program: 6O 0 C (2 minute)-10° C/minute-100°C (0 minute)-20 o C/minute-250° C (10 minutes), Injector temperature: 200 0 C Detector (FID) temperature: 250 0 C.
  • Step 1 Preparation of Compound VI (Le., 3-(3-trifluoromethyl phenyl)propynol)
  • reaction mixture was cooled to room temperature (20-25° C), and 400 mL of /erf-butyl methyl ether was added.
  • the resulting mixture was then filtered through a celite pad, and the filtrate was separated.
  • the aqueous layer was then washed two times with 200 mL of tert-buty ⁇ methyl ether, and the collected organic layers were dried and evaporated to yield 260 g of crude
  • Step 2 Preparation of Compound V ⁇ (Le., 3-(3-trifluoromethylphenyl)propan-l-ol
  • Step 3 Preparation of Compound m (Le., 3-(3-trifluoromethylphenyI)propanal)
  • Step 1 Preparation of Compound VI (Le., 3- ⁇ 3-trifluoromethylphenyl)propynol)
  • Step 2 Preparation of Compound V ⁇ (Le., 3-(3-trifluoromethylphenyl)propan-l-ol
  • TEMPO 2,2,6,6-tetramethyl-l-piperidinyloxy free radical
  • the precipitated adduct was filtered, was suspended two times with 20 mL of toluene and was dried in vacuum to yield 14.8 g of the aldehyde adduct, which was used up without further purification.
  • 8.86 g (30.4 mmol) of the bisulphite adduct was suspended in 20 mL of water, and 40 mL of 10% sodium hydroxide solution were added with stirring until all solids were dissolved.
  • the obtained opaque solution was extracted six times with 20 mL of dichloromethane. The collected organic layers were dried and evaporated. In this way 4.46 g (71.9%) of the free aldehyde were obtained. Purity: 99.5%.
  • the above reaction mixture was not treated with sodium .
  • Example 3 Large scale preparation of Compound DI (Le., 3-(3-trifluoromethyl phenyl)propanal
  • Example S Preparation of Compound III (Le., 3-(3-trifluoromethylphenyl) propanal

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates, in general, to an improved process for preparing compounds (e.g., 3-(3-trifluoromethylphenyl)propanal (Compound III, below)), which are key intermediates for jjhe synthesis of cinacalcet its salts and/Or solvates thereof, as well as the use of such compounds prepared by such process for the preparation of cinacalcet and/or its salts or solvates.(I).

Description

PROCESSES FOR PREPARING INTERMEDIATE COMPOUNDS USEFUL FOR THE PREPARATION OF CINACALCET
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to United States Provisional Application No. 60/811,786, filed June 8, 2006, application which is expressly incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION 1. Field of the Invention
The invention relates, in general, to an improved process for preparing compounds {e.g., 3-(3-trifluoromethylphenyl)propanal (Compound III, below)), which are key intermediates for the synthesis of cinacalcet, its salts and/or solvates thereof, as well as the use of such compounds prepared by such process for the preparation of cinacalcet and/or its salts or solvates.
Figure imgf000002_0001
2. Discussion of the Related Art
Cinacalcet is a commercially marketed pharmaceutically active substance known to be useful for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Cinacalcet is the international commonly accepted name for N-[I -(RH")- 1-naphthy l)ethyl]73-[3- (trifluoromethyl)phenyl]-l-aminopiOpane hydrochloride, which has an empirical formula of C22H22F3NΗCI, a molecular weight of 393.9 and has the structural formula (I):
Figure imgf000002_0002
U.S. Patent No. 6,011,068 generally describes cinacalcet and its pharmaceutically acceptable acid addition salts, but does not provide any examples for the preparation of the same. U.S. Patent No. 6,211,244 describes cinacalcet and its pharmaceutically acceptable acid chloride addition salt, but does not provide any examples for the preparation of cinacalcet and/or cinacalcet hydrochloride.
Drugs 2002, 27(9), 831-836 discloses a synthetic scheme for preparing cinacalcet hydrochloride according to the general procedure described in U.S. Patent No. 6,211,244. This disclosed synthetic route is illustrated in Scheme 1, below.
Figure imgf000003_0001
Scheme 1
In this regard, several processes for preparing Compound III {i.e., 3-(3-trifluoro methylphenyOpropanal) have been described in the literature.
European Patent EP 0 194 764 discloses a process for preparing Compound III in which Compound IV {i.e., 3-trifluoromethyIbromobenzene) is reacted with Compound V {i.e., propargyl alcohol) using bis(triphenylphosphine)palladium chloride and cuprous iodide in triethylamine, followed by catalytic hydrogenation to give the corresponding alcohol (compound VII). Compound VII is then converted to Compound III by a Swern oxidation. This synthetic procedure is illustrated in Scheme 2, below.
Figure imgf000003_0002
Scheme 2 In Tetrahedron Letters 2004, 45(45), 8355-58, Compound HI is prepared from Compound IX (Le., 3-trifluoromethylcinnamic acid) by reduction of the double bond and reduction of the carboxylic acid group into the corresponding alcohol followed by a Swern oxidation reaction, as illustrated in Scheme 3, below.
Figure imgf000004_0001
Scheme 3
An alternative process for preparing Compound III is described in Journal of Medicinal Chemistry 1968, 11, 1258-62.
SUMMARY OF THE INVENTION
The invention relates, in general, to an improved process for preparing compounds (e.g., 3-(3-trifluoromethylphenyl)propanal (Compound HI)), which are key intermediates for the synthesis of cinacalcet, its salts and/or solvates thereof, as well as the use of such compounds prepared by such process for the preparation of cinacalcet and/or its salts or solvates.
Figure imgf000004_0002
The invention provides an improved process for preparing Compound III. Namely, the process of the invention for preparing Compound HI and similar compounds obviates the need to employ a Swern oxidation step (as required in the above-described processes) and therefore avoids the need to employ low temperature oxidation reactions as well as the unpleasant odors associated with such procedures. In particular, the process of the invention includes oxidation of Compound VIl with an oxidizing agent using a nitroxyl compound as catalyst in an inert solvent.
The invention further includes a process for preparing Compound VII from compound VI. The invention further provides a process for preparing Compound VI (i.e., 3-(3- trifluoromethylphenyl)propynol) using lower amounts of catalyst and in which the catalyst can be at least partially recycled.
The processes of the invention are clean, fast, have high volume efficacy and require no chromatographic purifications. These characteristics of the processes of the invention make them very suitable for industrial scale up.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
The invention relates, in general, to an improved process for preparing compounds (e.g., 3-(3-trifluoromethylphenyl)propanal (Compound HI)), which are key intermediates for the synthesis of cinacalcet, its salts and/or solvates thereof, as well as the use of the such compounds prepared such process for the preparation of cinacalcet and/or its salts or solvates. In particular, the process of the invention includes oxidation of Compound VII with an oxidizing agent using a nitroxyl compound as catalyst in an inert solvent to yield Compound III. A suitable nitroxyl compound for use in the invention includes TEMPO (2,2,6,6,-tetramethy-l-piperidinyloxy free radical). A suitable oxidation agent for use in the invention includes sodium hypochlorite. Suitable inert solvents for use in the invention include any solvent that does not take part in the reaction. Preferred inert solvents include, for example, cyclic or acyclic alkanes (e.g., hexane, heptane, methylcyclohexane), aromatic solvents (e.g., toluene), halogenated solvents (e.g., dichloromethane, dichloroethane, chloroform), esters (e.g., ethyl acetate, butyl acetate, isopropyl acetate) or ethers (e.g., diethyl ether, tetrahydrofuran or tert-butyl methyl ether) and/or mixtures thereof. Preferably, the oxidation reaction is performed using between approximately 0.9 to approximately 2.0 moles of sodium hypochlorite per mol of Compound VII, preferably approximately 1.05 moles. It was furthermore found to be advantageous to add the sodium hypochlorite in portions to the reaction mixture. Preferably, approximately 1 mole of sodium hypochlorite per mol of Compound VII was added to the reaction mixture in a first portion, and after a period of stirring, a second portion of approximately 0.05 moles of sodium hypochlorite per mol of Compound VII was added.
The reaction can optionally be performed using potassium bromide as a regenerating agent of the nitroxyl compound used as catalyst. Preferably, the oxidation reaction is conducted using a range of temperatures of approximately 5° C to approximately 25° C and for a time of approximately 10 to approximately 60 minutes. More preferably below 15 0C, and for a time of approximately 20 to approximately 60 minutes.
Optionally, Compound III can be treated with sodium bisulphite to obtain a bisulphite adduct that can be further converted to a purified Compound III. Alternatively, Compound III can be purified by distillation under vacuum.
Compound VII can be obtained according to the process described in the European Patent EP 0 194 764 (see Scheme 2, above). Alternatively, the reaction of Compound IV with Compound V (Le., propargyl alcohol) can be performed using 10% Pd/C catalyst, triphenyl phosphine, copper (I) iodide and diisopropylamine, to yield Compound VT. Compound VI can readily be converted to Compound VΗ via catalytic hydrogenation in the presence of Pd/C catalyst
Another aspect of the invention includes the use of Compound III obtained according to the above-described processes for producing cinacalcet and/or its pharmaceutically acceptable salts and/or solvates thereof. The various embodiments of the invention having thus been generally described, several examples will hereafter be discussed to illustrate the inventive aspects more fully.
Specific Examples
The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention. General Experimental Conditions: Gas Chromatography Method
The gas chromatographic separation was carried out using a RTX-50, 30m x 0.32 mm x 0.25 μm column, a head pressure of 10 psi and helium as the carrier gas. Temperature program: 6O0C (2 minute)-10° C/minute-100°C (0 minute)-20oC/minute-250° C (10 minutes), Injector temperature: 2000C Detector (FID) temperature: 2500C.
Example 1: Preparation of 3-(3-trifluoromethylphenyl)propanal
Step 1: Preparation of Compound VI (Le., 3-(3-trifluoromethyl phenyl)propynol)
Figure imgf000007_0001
Compound VI
Under argon atmosphere, 266.4 g (1184 mmol) of 3-trifluoromethylbromobenzene, 85.0 g (1516 mmol) of propargyl alcohol, 118.4 g (1.4 mol) of diisopropyl amine, 22.53 g (0.118 mol) of copper (I) iodide, 4.73 g (4.44 mmol) of 10% Pd/C (Selcat Q6) and 31.5 g (0.118 mol) of triphenyl phosphine were dispersed in 1000 mL of distilled water. The reaction mixture was then stirred and refluxed overnight, and the conversion was checked by GC. Next, the reaction mixture was cooled to room temperature (20-25° C), and 400 mL of /erf-butyl methyl ether was added. The resulting mixture was then filtered through a celite pad, and the filtrate was separated. The aqueous layer was then washed two times with 200 mL of tert-buty\ methyl ether, and the collected organic layers were dried and evaporated to yield 260 g of crude
Compound VI as a dark oil. The resulting crude Compound VI was then purified by vacuum distillation. Purity by GC was approximately 83%. 1H NMR data (200 MHz, CDCl3, ppm): 3.09 (s, IH), 4.52 (s, 2H), 7.39-7.46 (m, IH), 7.52-7.59 (m, 2H), 7.67 (s, IH).
Step 2: Preparation of Compound VΩ (Le., 3-(3-trifluoromethylphenyl)propan-l-ol
Figure imgf000007_0002
Compound VII
To a solution of 57.5 g (288 mmol) of Compound VI in 60 mL of methanol, 1.4 g of 10% Pd/C (Selcat Q6) was added. The reaction mixture was hydrogenated at a temperature of 42-450C and a pressure of 5 bars until all starting material was reacted (approximately 5 hours). The catalyst was removed by filtration and washed with a small amount of methanol. The solution obtained was then evaporated in vacuo. The resulting crude product (49.4 g, 84.1%) was purified by vacuum distillation to yield 41.9 g (Yield: 71.2%) of pure Compound VII product as a nearly colorless oil (bp.: 58-60° C/ 1.1-1.5 mbar). 1H NMR data (200 MHz, CDCl3, ppm): 1.87 (q, 2H), 2.73 (t, 2H), 3.37 (s, IH), 3.64 (t, 2H), 7.33-7.45 (m, 4H).
Step 3: Preparation of Compound m (Le., 3-(3-trifluoromethylphenyI)propanal)
Figure imgf000008_0001
Compound III
To a solution of 10 g (48 mmol) of Compound VII, 76.6 mg of TEMPO (2,2,6,6- tetrarnethyl-1-piperidinyloxy free radical) and 234 mg of potassium bromide in 70 mL methylene chloride was added 220 mL (pH=9.5) of sodium hypochlorite solution over 20 minutes at 10- 15° C with stirring. After five minutes of additional stirring, the organic layer was separated. The aqueous layer was extracted twice with 40 mL of methylene chloride, and the collected organic layers were dried and evaporated to yield 1O g of crude Compound HI as a yellowish liquid. Yield: 100%; purity (determined by GC): 90.3%, contains 8.25% of Compound VII. 1H NMR data (200 MHz, CDCl3, ppm): 2.81 (t, 2H), 3.00 (t, 2H), 7.37-7.46 (m, 4H), 9.80 (s, IH).
Example 2: Preparation of 3-(3-trifluoromethylphenyl)propaπal
Step 1: Preparation of Compound VI (Le., 3-{3-trifluoromethylphenyl)propynol)
Figure imgf000008_0002
Compound VI Under argon atmosphere, 23.0 g (102.2 mmol) of 3-trifluoromethylbromobenzene, 7.34 g
(130.85 mmol) of propargyl alcohol, 15.32 g (182.83 mmol) of diisopropyl amine, 2.92 g (15.3 mmol) of copper (I) iodide, 0.61 g (0.570 mmol) of 10% Pd/C (Selcat Q6) and 4.02 g (15.32 mmol) of triphenyl phosphine were dispersed in 80 mL of distilled water. The reaction mixture was then stirred and refluxed overnight, and the conversion was checked by GC. Next, the reaction mixture was cooled to room temperature (20-25° C), and 40 mL of terf-butyl methyl ether were added. The resulting mixture was then filtered through a celite pad, and the filtrate was separated. The aqueous layer was then washed two times with 50 mL of /erf-butyl methyl ether, and the collected organic layers were dried and evaporated to yield 45.3 g of crude Compound VI as a dark oil. The resulting crude Compound VI was then purified by vacuum distillation. In this way 14.7 g of the product were obtained, b.p. 120-125°C/3.2-3.8mbar.
Step 2: Preparation of Compound VΗ (Le., 3-(3-trifluoromethylphenyl)propan-l-ol
Figure imgf000009_0001
Compound VTI To a solution of 14.5 g (72.5 mmol) of purified 3-(3-trifluoromethyIphenyl) propynol in
50 mL of 2-propanol, 0.38 g of 10% Pd/C (Selcat Q6) was added. The reaction mixture was hydrogenated at a temperature of 42-450C and a pressure of 5 bars until all starting material was reacted (approximately 5 hours). The catalyst was removed by filtration and washed with a small amount of 2-propanol. The obtained solution was then evaporated in vacuo. The resulting crude product (14.5 g, 100.0%) was purified by vacuum distillation to yield 10.5 g (Yield: 72.1%) of pure Compound VII product as a nearly colorless oil (bp.: 58-60° C/l .1-1.5 mbar).
Step 3:Preparation of Compound III (Le., 3-(3-trifluoromethyIphenyl)propanai
Figure imgf000009_0002
Compound III To a mixture of the solution of 10 g (48 mmol) of Compound VII, 76.6 mg of
TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxy free radical) in 70 mL of toluene and the solution of 234 mg of potassium bromide in 8 mL of water, 93 mL (pH=9.5) of sodium hypochlorite solution were added over 10 minutes at 10-15° C with stirring. After five minutes of additional stirring, the organic layer was separated. The aqueous layer was extracted twice with 30 mL of toluene, and the collected organic layers were stirred with a solution of 71 g of sodium bisulphite in 100 mL of water at 100-110° C until all of the aldehyde bisulphite adduct was separated as white solid. The precipitated adduct was filtered, was suspended two times with 20 mL of toluene and was dried in vacuum to yield 14.8 g of the aldehyde adduct, which was used up without further purification. Next, 8.86 g (30.4 mmol) of the bisulphite adduct was suspended in 20 mL of water, and 40 mL of 10% sodium hydroxide solution were added with stirring until all solids were dissolved. The obtained opaque solution was extracted six times with 20 mL of dichloromethane. The collected organic layers were dried and evaporated. In this way 4.46 g (71.9%) of the free aldehyde were obtained. Purity: 99.5%. Alternatively, when the above reaction mixture was not treated with sodium . bisulphite then the aldehyde solution was evaporated and the obtained 8.5 g (87.6%) of the crude aldehyde were distilled in fine vacuum. In this way 5.14 g (53.0%) of the aldehyde were obtained as slightly yellowish oil. Purity: 98.0%, b.p. 53-54° C /2.3-2.5 mbar.
Example 3: Large scale preparation of Compound DI (Le., 3-(3-trifluoromethyl phenyl)propanal
Figure imgf000010_0001
Compound HI
In a 630 L glass-lined reaction vessel, purged with nitrogen and equipped with a pitched blade impeller, were added (in sequence): 0.74 Kg (6.2 mol) of potassium bromide, 0.24 Kg (1.5 mol) of TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxy free radical), 137 Kg of toluene, 31.6 Kg (155 mol) of Compound VII, 68 Kg of toluene, and 29 Kg of water. The mixture was stirred and cooled to 0-5° C to give a brownish solution. To this mixture, 115 Kg (155 mol) of 10% w/w aqueous sodium hypochlorite solution (previously adjusted to pH 9.5 using saturated sodium hydrogen carbonate) was added under nitrogen at a rate that maintained the reaction temperature below 15° C. Once addition was complete, the reaction mixture was stirred at 10-15° C for 30 minutes. After this period, a further 5.7 Kg (7.7 mol) of 10% w/w aqueous sodium hypochlorite solution at pH 9.5 was added and the mixture was stirred for an additional 30 minutes at 10-15° C. The mixture was allowed to stand and the upper organic phase and the lower aqueous phase were separated. The aqueous phase was extracted by stirring for 30 minutes at 10-15° C with 55 Kg of toluene. This extraction was repeated with a further 55 Kg of toluene and the organic phases thus obtained were combined with the organic phase obtained previously. Acidified potassium iodide solution (157 Kg; 2.4% w/w) was then added to the stirred, combined organic phases at 10-15° C. The organic phase turned deep orange during the addition. The mixture was stirred for a total of 30 minutes at 10-15° C and subsequently the reddish, organic phase was separated. Sodium thiosulphate solution (167 Kg; 10% w/w aqueous) was next added to the stirred organic phase at 10-15° C. The organic phase turned from deep orange to colorless during the addition. The mixture was stirred for a total of 30 minutes at 10-15° C and subsequently the pale yellow, organic phase was separated. Sodium hydrogen carbonate solution (157.9 Kg, 5% w/w) was next added to the stirred organic phase at 10-15° C. The resulting mixture was stirred for a total of 30 minutes at 10-15° C and subsequently the pale yellow, organic phase was separated. Deionized water (158 Kg) was next added to the stirred organic phase at 10-15° C. The resulting mixture was stirred for a total of 30 minutes at 10-15° C and subsequently the pale yellow, organic phase, was separated. The organic phase was then concentrated by distilling off the toluene under vacuum at a temperature of ca. 40° C. This gave crude 3-[3- (trifluoromethyl)phenyl]propanal (Compound III) as a clear, yellow oil. The crude product was subsequently distilled under vacuum, collecting pure Compound III as a pale yellow oil in the temperature range of 85-105° C at about 5 mbar. Yield: 26.0 Kg (83.1%).
Example 4: Preparation of Compound III (Le., 3-(3-trifluoromethylphenyl) propaπal
Figure imgf000011_0001
Compound m
This example was carried out following the conditions of Example 3, but adding instead a total of 1.05 moles of sodium hypochlorite per mol of Compound (VII) in one single portion, Compound III was obtained with yield of 73.0%. Example S: Preparation of Compound III (Le., 3-(3-trifluoromethylphenyl) propanal
Figure imgf000012_0001
Compound ITt
This example was carried out following the conditions of Example 3, but adding instead a total of 1.10 moles of sodium hypochlorite per mol of Compound (VII) in one single portion, Compound IH was obtained with yield of 69.0%.
Example 6: Preparation of Compound IQ (Le., 3-(3-trifluoromethylphenyl) propanal
Figure imgf000012_0002
Compound III
This example was carried out following the conditions of Example 3, but adding instead a total of 1.30 moles of sodium hypochlorite per mol of Compound (VII) in one single portion, Compound III was obtained with yield of 60.0%. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

Claims

1. A process for preparing 3-(3-trifluoromethylphenyl)propanal (Compound III), comprising
Figure imgf000013_0001
oxidation of Compound VII
Figure imgf000013_0002
(VII) with an oxidizing agent using a nitroxyl compound as catalyst, in the presence of an inert solvent.
2. The process of claim 1 , wherein said oxidizing agent is sodium hypochlorite.
3. The process of claim 2, wherein said sodium hypochlorite comprises approximately 1.05 moles of sodium hypochlorite per mole of Compound VII.
4. The process of claim 2, wherein said sodium hypochlorite is added in at least two portions.
5. The process of claim 4, wherein said sodium hypochlorite is added in two portions.
6. The process of claim 5, wherein a first portion of sodium hypochlorite comprises approximately 1.0 moles sodium hypochlorite per mole of Compound VII, and a second portion of sodium hypochlorite comprise approximately 0.05 moles of sodium hypochlorite per mole of Compound VII.
7. The process of claim 1, wherein said nitroxyl compound is TEMPO (2,2,6,6,- tetramethy-l-piperidinyloxi free radical).
8. The process of claims 1 or 7, further comprising the use of potassium bromide as a regenerating agent of the nitroxyl compound.
9. The process of claim 1, wherein said oxidation occurs at a temperature of approximately 5° C to approximately 25° C.
10. The process of claim 1, wherein said oxidation occurs at a temperature of approximately 100 C to approximately 15° C.
11. The process of claim 1, wherein said oxidation occurs at a temperature below approximately 15° C.
12. The process of claim 1, wherein said inert solvent is any solvent that does not take ' part in the reaction.
13. The process of claim 1 , wherein said inert solvent is at least one of a cyclic alkane, an acyclic alkane, an aromatic solvent, a chlorinated solvent, an ester, an ether and mixtures thereof.
14. The process of claim 1, wherein said inert solvent is at least one of hexane, heptane, methylcyclohexane, toluene, dichloromethane, dichloroethane, chloroform, ethyl acetate, butyl acetate, isopropyl acetate, diethyl ether, tetrahydrofiiran, tert-butyl methyl ether and mixtures thereof.
15. The process of claim 1, wherein said oxidation occurs for approximately 10 to approximately 60 minutes.
16. A process for preparing cinacalcet, its pharmaceutically acceptable salts and/or solvates thereof comprising converting Compound III made according to the processes of any of claims 1- 15 into cinacalcet, its pharmaceutically acceptable salts and/or solvates thereof.
17. Cinacalcet, its salts and/or solvates thereof prepared by the process of claim 16.
18. A formulation containing cinacalcet, its salts and/or solvates thereof according to claim 17.
19. A process for preparing Compound VII comprising: i. reacting Compound IV,
Figure imgf000014_0001
with Compound V,
SOH
(V) using 10% PdVC catalyst, triphenyl phosphine, copper (I) iodide and diisopropylamine, to yield Compound VI; and
Figure imgf000015_0001
ii. converting Compound VI into Compound VII via catalytic hydrogenation.
20. The process of claim 1, wherein said Compound VII is prepared by a process comprising: i. reacting Compound IV,
Figure imgf000015_0002
(IV) with Compound V,
-OH
(V) using 10% Pd/C catalyst, triphenyl phosphine, copper (I) iodide and diisopropylamine, to yield Compound VI; and
Figure imgf000015_0003
ii. converting Compound VI into Compound VII via catalytic hydrogenation.
PCT/IB2007/003346 2006-06-08 2007-06-08 Processes for preparing intermediate compounds useful for the preparation of cinacalcet WO2008035212A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US12/303,903 US20100267988A1 (en) 2006-06-08 2007-06-08 Processes for preparing intermediate compounds useful for the preparation of cinacalcet
CA002659153A CA2659153A1 (en) 2006-06-08 2007-06-08 Processes for preparing intermediate compounds useful for the preparation of cinacalcet
JP2009513799A JP2009539823A (en) 2006-06-08 2007-06-08 Process for preparing useful intermediate compounds for the preparation of cinacalcet
EP07858859A EP2041056A2 (en) 2006-06-08 2007-06-08 Processes for preparing intermediate compounds useful for the preparation of cinacalcet
IL195757A IL195757A0 (en) 2006-06-08 2008-12-07 Processes for preparing intermediate compounds useful for the preparation of cinacalcet

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81178606P 2006-06-08 2006-06-08
US60/811,786 2006-06-08

Publications (2)

Publication Number Publication Date
WO2008035212A2 true WO2008035212A2 (en) 2008-03-27
WO2008035212A3 WO2008035212A3 (en) 2008-08-21

Family

ID=39200909

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/003346 WO2008035212A2 (en) 2006-06-08 2007-06-08 Processes for preparing intermediate compounds useful for the preparation of cinacalcet

Country Status (8)

Country Link
US (1) US20100267988A1 (en)
EP (1) EP2041056A2 (en)
JP (1) JP2009539823A (en)
CN (1) CN101500976A (en)
AR (1) AR061310A1 (en)
CA (1) CA2659153A1 (en)
IL (1) IL195757A0 (en)
WO (1) WO2008035212A2 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010067204A1 (en) 2008-12-08 2010-06-17 Actavis Group Ptc Ehf Highly pure cinacalcet or a pharmaceutically acceptable salt thereof
WO2010128388A2 (en) 2009-05-08 2010-11-11 Aurobindo Pharma Limited An improved process for the preparation of intermediate compounds useful for the preparation of cinacalcet
WO2011029833A1 (en) 2009-09-10 2011-03-17 Zach System S.P.A. Process for preparing cinacalcet
WO2012007954A1 (en) 2010-07-16 2012-01-19 Hetero Research Foundation Process for cinacalcet hydrochloride
WO2013075679A1 (en) 2011-11-25 2013-05-30 Zentiva, K.S. A method of producing cinacalcet
WO2014016847A1 (en) 2012-07-25 2014-01-30 Tyche Industries Limited A process for the preparation of cinacalcet hydrochloride and its intermediate
US9290439B2 (en) 2012-09-07 2016-03-22 Produits Chimiques Auxiliaires Et De Synthese Process for preparing cinacalcet and pharmaceutically acceptable salts thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102060679B (en) * 2009-11-18 2014-11-19 中国中化股份有限公司 Method for preparing aryl propanal derivatives
CN102060675A (en) * 2009-11-18 2011-05-18 中国中化股份有限公司 3-aryl-1-propylene alcohol ether and preparation method thereof
IT1396623B1 (en) * 2009-11-26 2012-12-14 Dipharma Francis Srl PROCEDURE FOR THE PREPARATION OF CINACALCET AND ITS INTERMEDIATES
CN103664577B (en) * 2012-09-06 2015-04-08 北京万生药业有限责任公司 Preparation method of cinacalcet intermediate
CN113121388B (en) * 2021-03-29 2021-11-12 西华大学 Cinacalcet intermediate and synthetic method of cinacalcet hydrochloride

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0194764A1 (en) * 1985-02-18 1986-09-17 The Wellcome Foundation Limited Pesticidal compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0194764A1 (en) * 1985-02-18 1986-09-17 The Wellcome Foundation Limited Pesticidal compounds

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DE FRANCISCO ANGEL L M: "Cinacalcet HCl: a novel therapeutic for hyperparathyroidism" EXPERT OPINION ON PHARMACOTHERAPY, ASHLEY, LONDON,, GB, vol. 6, no. 3, March 2005 (2005-03), pages 441-452, XP008082433 ISSN: 1465-6566 *
NOOY DE A E J ET AL: "ON THE USE OF STABLE ORGANIC NITROXYL RADICALS FOR THE OXIDATION OF PRIMARY AND SECONDARY ALCOHOLS" SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE, no. 10, 1996, pages 1153-1174, XP009071799 ISSN: 0039-7881 *
WANG X ET AL: "Synthesis of Cinacalcet congeners" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 45, no. 45, 1 November 2004 (2004-11-01), pages 8355-8358, XP004593872 ISSN: 0040-4039 cited in the application *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010067204A1 (en) 2008-12-08 2010-06-17 Actavis Group Ptc Ehf Highly pure cinacalcet or a pharmaceutically acceptable salt thereof
WO2010128388A2 (en) 2009-05-08 2010-11-11 Aurobindo Pharma Limited An improved process for the preparation of intermediate compounds useful for the preparation of cinacalcet
WO2011029833A1 (en) 2009-09-10 2011-03-17 Zach System S.P.A. Process for preparing cinacalcet
US8637708B2 (en) 2009-09-10 2014-01-28 Zach System S.P.A. Process for preparing cinacalcet
WO2012007954A1 (en) 2010-07-16 2012-01-19 Hetero Research Foundation Process for cinacalcet hydrochloride
US20130178654A1 (en) * 2010-07-16 2013-07-11 Hetero Research Foundation Process for cinacalcet hydrochloride
US8921606B2 (en) 2010-07-16 2014-12-30 Hetero Research Foundation Process for cinacalcet hydrochloride
WO2013075679A1 (en) 2011-11-25 2013-05-30 Zentiva, K.S. A method of producing cinacalcet
WO2014016847A1 (en) 2012-07-25 2014-01-30 Tyche Industries Limited A process for the preparation of cinacalcet hydrochloride and its intermediate
US9290439B2 (en) 2012-09-07 2016-03-22 Produits Chimiques Auxiliaires Et De Synthese Process for preparing cinacalcet and pharmaceutically acceptable salts thereof
US9598350B2 (en) 2012-09-07 2017-03-21 Produits Chimiques Auxiliaries Et De Synthese Process for preparing cinacalcet and pharmaceutically acceptable salts thereof

Also Published As

Publication number Publication date
IL195757A0 (en) 2009-09-01
WO2008035212A3 (en) 2008-08-21
JP2009539823A (en) 2009-11-19
CA2659153A1 (en) 2008-03-27
AR061310A1 (en) 2008-08-20
US20100267988A1 (en) 2010-10-21
CN101500976A (en) 2009-08-05
EP2041056A2 (en) 2009-04-01

Similar Documents

Publication Publication Date Title
EP2041056A2 (en) Processes for preparing intermediate compounds useful for the preparation of cinacalcet
JP4773436B2 (en) Method for preparing cinacalcet hydrochloride
JP2008074754A (en) METHOD FOR PRODUCING trans-1,4-DIAMINOCYCLOHEXANE
Paolucci et al. Approach to a better understanding and modeling of (S)-dihydrofuran-2-yl,(S)-tetrahydrofuran-2-yl-, and furan-2-yl-β-dialkylaminoethanol ligands for enantioselective alkylation
JP3812598B2 (en) Method for producing polyhydric alcohol
JPH11140022A (en) Jasmonic acid-based compound and its production
JP2008063335A (en) Method for producing 1,2-diol from carbonyl compound
JP4020141B2 (en) Method for producing 1-acetoxy-3- (substituted phenyl) propene compound
JP3435475B2 (en) Method for producing 1,2-propanediol
JP2003313153A (en) Method for producing optically active 2-acylated 1,2-diol compound derivative
JP2001278875A (en) Method for producing 3-fluoroalkoxymethyl-3- alkyloxetane
JP2006513246A (en) Production of water-soluble β-hydroxynitrile
EP1326821A2 (en) Method of making fluorinated alcohols
JP4409057B2 (en) Method for producing benzenedimethanol compound
JPH0892150A (en) Production of 5(e), 8(z), 11(z)-tetradecatrien-2-one
JP3089672B2 (en) Diol compound having cyclohexane ring and method for producing diol compound having cyclohexane ring
JP2009155232A (en) Method for producing mixture of 2-(1-hydroxyalkyl)cycloalkanone and dehydrated material of the same
US9090533B2 (en) Process for producing 4-cyclohexyl-2-methyl-2-butanol
JP2002138084A (en) Manufacturing method of ethers by using 3-alkyl-3- hydroxymethyloxetane as raw material
JP4286694B2 (en) Novel Grignard reagent and method for producing aliphatic alkynyl Grignard compound using the same
JP2838226B2 (en) α- (4- (1-hydroxy-2-methylpropyl) phenyl) ethanol
JP5564088B2 (en) Process for producing trans-1,4-diaminocyclohexane
JP4243397B2 (en) Novel unsaturated secondary alcohol and process for producing the same
WO1999058488A1 (en) Improved process for the preparation of trifluoromethyl containing derivatives
JPH01213250A (en) Tertiary butyl akynol

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780029675.7

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 195757

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2659153

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2009513799

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 122/CHENP/2009

Country of ref document: IN

Ref document number: 2007858859

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: RU

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

Ref document number: 07858859

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 12303903

Country of ref document: US