Efficient Synthesis of Cinacalcet Hydrochloride

Bijukumar, Gopinathenpillai; Maloyesh, Biswas; Bhaskar, Bhirud Shekhar; Rajendra, Agarwal

doi:10.1080/00397910801928541

Cited by 22 publications

(21 citation statements)

References 5 publications

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“…Thiel et al [3] reported a practically synthetic route via hydrogenation, amide coupling, reduction, and salification (Scheme 2). A similar route was also reported by Bijukumar et al [4] During our development of cinacalcet hydrochloride 1, high-performance liquid chromatographic (HPLC) analysis of crude product revealed other three impurities ranging from 0.05 to 0.20%, besides the starting materials and unreacted intermediates. The International Conference of Harmonization (ICH) has published guidelines on impurities in new drug substances, products, and residual solvents that state that the acceptable levels for known and unknown compounds in a final drug candidate must be less than 0.15% and 0.10%, respectively, and the impurities need to be extensively controlled and prepared for the quality controls of the main product.…”

Section: Introductionsupporting

confidence: 61%

“…The key intermediate 12 was obtained by Kishner-Wolff-Huang reduction in quantitative yield and treated with triflic anhydride and Et 3 N in anhydrous dichloromethane to give the triflate 13 in overall 67% yield. The ketone 14 was also obtained via Heck coupling and hydrolization, directly reacted with the amine 5 in Ti(O-i-Pr) 4 , and reduced by NaBH 4 in methanol to get the crude 3, which was further salified and recrystallized in acetonitrile to get 3 with the purity of 97.88% by HPLC. The naphthalen-2-yl related substance 4 is a structural isomer of cinacalcet hydrochloride 1 and generated due to presence of 1-(2-naphthyl)ethylamine as an impurity in the key raw material 1-(1-naphthyl)ethylamine.…”

Section: Resultsmentioning

confidence: 99%

“…On one hand, because of the inductive effects in the formation of the imine, it decreased the dihydronaphthalene ring electron density and the offset of the p electron cloud, so as to result the polarization in the molecule and the reduction of the double bond by NaBH 4 . On the other hand, to catalyze the formation of the imine, Lewis acid Ti(O-i-Pr) 4 was added as solvent and the reactivity of NaBH 4 could be greatly enhanced in the presence of Lewis acid [7] (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

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Efficient Synthesis of Substances Related to Cinacalcet Hydrochloride via Heck Coupling

Fan

et al. 2014

Synthetic Communications

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Efficient synthetic methods to process substances related to cinacalcet hydrochloride 1, generated during the preparation, were described. The compounds were identified as [1-(7,8-dihydro-naphthalen-1-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)-propyl]-amine hydrochloride 2,[1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)-propyl]-amine hydrochloride 3 and [1-(naphthalen-2-yl)-ethyl]-[3-(3-trifluoromethylphenyl)-propyl]-amine hydrochloride 4. All were prepared from commercially available materials in several linear steps and characterized by their respective spectral data.

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Section: Introductionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Efficient Synthesis of Substances Related to Cinacalcet Hydrochloride via Heck Coupling

Fan

et al. 2014

Synthetic Communications

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“…The piperidine and pyridine, [20,21] efficient organocatalysts for general Knoevenagel-Doebner reactions, showed no catalytic activity at room temperature (Entries 2 and 3, Table 1). For β-alanine, a reported efficient catalyst for the Knoevenagel-Doebner reaction under refluxing condition, [22] only moderate amount of product was produced in EtOH (Entry 4, Table 1).…”

Section: Resultsmentioning

confidence: 97%

β‐Alanine‐DBU: A Highly Efficient Catalytic System for Knoevenagel‐Doebner Reaction under Mild Conditions

Zhu

Lei²,

Miao

et al. 2012

Chin. J. Chem.

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A mild and efficient Knoevenagel-Doebner reaction from malonic acid and a wide range of aldehydes was catalyzed by a catalytic system consisting of β-alanine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), affording the corresponding (E)-α,β-unsaturated carboxylic acids in good to excellent yields and with high stereoselectivity. The advantage of the method is that the reaction could proceed smoothly at ambient temperature so that it can tolerate a variety of functional groups and avoid unnecessary side reactions.

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“…The principle method that has been used to prepare cinacalcet has involved the coupling of the chiral amine (R)-12 with the phenylpropanoic acid derivative 22 to form an amide that is isolated and then subsequently reduced (Scheme 2). [9][10][11][12][13] Ortiz-Marciales and co-workers developed a method for the asymmetric synthesis of non-racemic primary amines based on an amido-spiroborate catalyzed reduction of O-benzyloximes. 11 This methodology was used to synthesize the necessary amine (R)-12.…”

mentioning

confidence: 99%

A two-step, one pot preparation of amines via acyl succinimides. Synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568

Gooodman

Janci

Onwodi

et al. 2015

Tetrahedron Letters

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a b s t r a c tA method has been developed for the preparation of amines through a process of coupling acyl succinimides derived from commercially available carboxylic acids with amines to afford the corresponding amides. These amides are then reduced in situ with either diisobutylaluminum hydride or lithium aluminum hydride. The reaction tandem of the coupling reaction followed by the reduction affords the amine in fair to good yields after purification by flash chromatography. This one-pot, two reaction tandem process has been successfully applied to the synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568.Ó 2015 Elsevier Ltd. All rights reserved.Acyl succinimides are activated amides that can be readily prepared by the reaction of acyl chlorides with succinimide or by the reaction of carboxylic acids with carbodiimides and succinimide. 1 These compounds have received little attention, but have the potential for use in a variety of applications. Reductive amination is one of the most common methods employed for the synthesis of amines. There was interest in employing the acyl succinimides in a two-step, one pot process for the synthesis of amines by an acyl coupling/reduction tandem (Fig. 1). The process would be a carboxyl equivalent of reductive amination. 2 The utility in this methodology would involve the conversion of the carboxylic acid into an acyl succinimide for the coupling/reduction process. This would potentially require less work than converting the carboxylic acid to the aldehyde for the purpose of a reductive amination. This methodology would not be viable with other carboxyl derivatives. The formation of an amide from an acyl chloride 3 and an amine would generate the protonated scavenger base (e.g., Et 3 NHCl) that would react violently with any reducing agents in the second stage of the reaction. Another example of an incompatible process would involve the use of a carbodiimide (e.g., DCC, DMAP) to couple a carboxylic acid and an amine. 4 The resultant amide would be formed along with N,N 0 -dicyclohexylurea. The urea side product would react with any reducing agent and would complicate the reaction mixture. Activated esters such as p-nitrophenyl esters, 5 N-hydroxysuccinimide esters, 6 or acyl imidazoles 7 would also involve problematic features, primarily the byproducts of the acyl coupling reacting with the reducing agent. In contrast, acyl succinimides can be easily prepared from carboxylic acids and readily undergo coupling with amines to afford the corresponding amide with succinimide as the only side product. These combined factors would be optimal for a one-pot process of coupling and reduction. The process of conducting the coupling/reduction tandem reactions in a single vessel is described as well as the synthesis of the calcimimetic agents cinacalcet (sensipar Ò ), NPS R-467 and NPS R-568.This work began with the preparation of 3-phenylpropanoyl succinimide (7) as a model compound for the acyl coupling/reduction tandem. This succinimide was prepared in 70% yiel...

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Efficient Synthesis of Cinacalcet Hydrochloride

Cited by 22 publications

References 5 publications

Efficient Synthesis of Substances Related to Cinacalcet Hydrochloride via Heck Coupling

Efficient Synthesis of Substances Related to Cinacalcet Hydrochloride via Heck Coupling

β‐Alanine‐DBU: A Highly Efficient Catalytic System for Knoevenagel‐Doebner Reaction under Mild Conditions

A two-step, one pot preparation of amines via acyl succinimides. Synthesis of the calcimimetic agents cinacalcet, NPS R-467, and NPS R-568

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