- Efficient synthesis of cinacalcet hydrochloride
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A new route to synthesize cinacalcet hydrochloride ((R)-α-methyl-N- [3-[3-(trifluoromethyl) phenyl] propyl]-1-naphthalene methane amine hydrochloride) has been described. The key steps include the Knoevenagel-Doebner condensation and the amide reduction under milder conditions. Copyright Taylor & Francis Group, LLC.
- Bijukumar, Gopinathenpillai,Maloyesh, Biswas,Bhaskar, Bhirud Shekhar,Rajendra, Agarwal
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- Synthesis of Enantioenriched Amines by Iron-Catalysed Amination of Alcohols Employing at Least One Achiral Substrate
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The synthesis of a broad range of enantioenriched amines by the direct Fe-catalysed coupling of amines with alcohols through the borrowing hydrogen strategy, while at least one of these substrates is achiral is reported. When starting from α-chiral amines and achiral alcohols, a wide range of enantioenriched amine products, including N-heterocyclic moieties can be obtained with complete retention of stereochemistry and the power of this method is demonstrated in the one-step synthesis of known pharmaceuticals from commercially available, simple enantiopure primary amines and achiral alcohols. It was also found that the use of β-branched enantioenriched primary alcohols and achiral amines as reaction partners leads to a partial loss of stereochemical integrity in the final product, however, a systematic optimization enabled partial retention of enantiopurity and possible parameters effecting for racemization were identified. (Figure presented.).
- Bottari, Giovanni,Afanasenko, Anastasiia,Castillo-Garcia, Antonio A.,Feringa, Ben L.,Barta, Katalin
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supporting information
p. 5436 - 5442
(2021/06/17)
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- Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines
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α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp3)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions. The reaction efficiently provides highly enantioenrichedN-alkyl sulfoximines (up to 99% yield and >99% ee) featuring secondary benzyl, propargyl, α-carbonyl alkyl, and α-cyano alkyl stereocenters. In addition, we have converted the masked α-chiral primary amines thus obtained to various synthetic building blocks, ligands, and drugs possessing α-chiral N-functionalities, such as carbamate, carboxylamide, secondary and tertiary amine, and oxazoline, with commonly seen α-substitution patterns. These results shine light on the potential of enantioconvergent radical cross-coupling as a general chiral carbon-heteroatom formation strategy.
- Cheng, Jiang-Tao,Dong, Xiao-Yang,Gu, Qiang-Shuai,Li, Zhong-Liang,Liu, Juan,Liu, Xin-Yuan,Luan, Cheng,Wang, Fu-Li,Wang, Li-Lei,Yang, Ning-Yuan,Zhang, Yu-Feng
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supporting information
p. 15413 - 15419
(2021/09/30)
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- Bisulfite Addition Compounds as Substrates for Reductive Aminations in Water
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Highly valued products resulting from reductive aminations utilizing shelf-stable bisulfite addition compounds of aldehydes can be made under aqueous micellar catalysis conditions. Readily available α-picolineborane serves as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished, and several applications to targets in the pharmaceutical industry are documented.
- Bailey, J. Daniel,Iyer, Karthik S.,Leahy, David K.,Li, Xiaohan,Lipshutz, Bruce H.,Thakore, Ruchita R.
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p. 7205 - 7208
(2021/09/22)
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- Preparation method of cinacalcet hydrochloride
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The invention discloses a method for preparing cinacalcet hydrochloride. The method comprises the following steps: performing condensation reaction on m-trifluoromethyl benzaldehyde serving as a starting raw material and acetaldehyde to prepare m-trifluoromethyl cinnamyl aldehyde, directly obtaining an oxalate intermediate from the m-trifluoromethyl cinnamyl aldehyde and R-1-(1-naphthyl) ethyl amine by a one-pot method to avoid impurity increase caused by separation of an unstable intermediate namely imine, desalting oxalate, carrying out Pd/C catalytic hydrogenation to obtain cinacalcet, and carrying out a reaction on cinacalcet and hydrochloric acid to finally obtain cinacalcet hydrochloride. The synthesis method disclosed by the invention is green, environment-friendly, economical and practical, simple to operate and more beneficial to industrial production.
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- BF3·Et2O as a metal-free catalyst for direct reductive amination of aldehydes with amines using formic acid as a reductant
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A versatile metal- and base-free direct reductive amination of aldehydes with amines using formic acid as a reductant under the catalysis of inexpensive BF3·Et2O has been developed. A wide range of primary and secondary amines and diversely substituted aldehydes are compatible with this transformation, allowing facile access to various secondary and tertiary amines in high yields with wide functional group tolerance. Moreover, the method is convenient for the late-stage functionalization of bioactive compounds and preparation of commercialized drug molecules and biologically relevant N-heterocycles. The procedure has the advantages of simple operation and workup and easy scale-up, and does not require dry conditions, an inert atmosphere or a water scavenger. Mechanistic studies reveal the involvement of imine activation by BF3and hydride transfer from formic acid.
- Fan, Qing-Hua,Liu, Xintong,Luo, Zhenli,Pan, Yixiao,Xu, Lijin,Yang, Ji,Yao, Zhen,Zhang, Xin
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supporting information
p. 5205 - 5211
(2021/07/29)
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- Asymmetric reduction method of nitrogen-phosphonyl protected imine
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The invention discloses an asymmetric reduction method of nitrogen phosphonyl protective imine. The nitrogen phosphonyl protective imine is reduced into chiral amine in a hydrogen atmosphere under theaction of a metal catalyst and alkali, and the metal catalyst is prepared from a metal iridium complex and a nitrogen-phosphorus chiral ligand. The method provided by the invention has the characteristics of high enantioselectivity, high yield and high conversion number (TON). The method can be used for synthesizing various substituted chiral amines, can be used as an important intermediate for preparing various medicines, and has important significance for industrial production of medicines.
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- Addition of Highly Polarized Organometallic Compounds to N-tert-Butanesulfinyl Imines in Deep Eutectic Solvents under Air: Preparation of Chiral Amines of Pharmaceutical Interest
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Highly polarized organometallic compounds of s-block elements are added smoothly to chiral N-tert-butanesulfinyl imines in the biodegradable d-sorbitol/choline chloride eutectic mixture, thereby granting access to enantioenriched primary amines after quantitatively removing the sulfinyl group. The practicality of the method is further highlighted by proceeding at ambient temperature and under air, with very short reaction times (2 min), enabling the preparation of diastereoisomeric sulfinamides in very good yields (74–98 %) and with a broad substrate scope, and the possibility of scaling up the process. The method is demonstrated in the asymmetric syntheses of both the chiral amine side-chain of (R,R)-Formoterol (96 % ee) and the pharmaceutically relevant (R)-Cinacalcet (98 % ee).
- Capriati, Vito,Cicco, Luciana,García-álvarez, Joaquín,González-Sabín, Javier,Perna, Filippo M.,Ríos-Lombardía, Nicolás,Salomone, Antonio,Vitale, Paola
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- A method for one-step synthesis of carboxylic acids with two extended carbon chains from olefins
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The invention relates to a method for one-step synthesis of carboxylic acid with two extended carbon chains from olefin, which comprises the following steps: under the protection of inert gas, sequentially adding an olefin substrate, a photocatalyst, a hydrogen atom transfer reagent, alpha-haloacetic acid, a reducing agent, a solvent and protonic acid into a reactor, and reacting at normal temperature under the irradiation of 25W blue light to obtain a reaction product; diluting, alkalizing, washing, acidifying and extracting the reaction product to obtain an organic phase; and finally, carrying out reduced pressure distillation and column chromatography on the organic phase to obtain a carboxylic acid product with two extended carbon chains; or carrying out reduced pressure distillation and column chromatography on the reaction product to obtain a carboxylic acid product with two extended carbon chains. The invention is simple to operate, direct synthesis conditions are mild, mutual conversion among various functional groups in the traditional carboxylic acid compound synthesis process is avoided, and the atom and step economy of the reaction is improved. Meanwhile, the method disclosed by the invention can also be applied to the simplified synthesis of the medicines cinacarbazide and tirofiban.
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Paragraph 0089-0091
(2020/10/12)
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- Preparation method of cinacalcet hydrochloride
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The invention relates to a preparation method of cinacalcet hydrochloride. The preparation method comprises the following steps: taking m-trifluoromethyl benzaldehyde, hydantoin and (R)-1-(1-naphthyl)ethylamine as raw materials, performing condensation, hydrolysis, amidation and reduction reaction to prepare cinacalcet, and reacting cinacalcet with hydrochloric acid to prepare cinacalcet hydrochloride. Compared with an existing synthesis method of cinacalcet hydrochloride, the preparation method is short in route and low in raw material cost, the adopted condensing agent is oxalyl chloride and thionyl chloride, which are low in price, the adopted reducing agent is sodium borohydride, which is low in price, a precious metal catalyst (palladium on carbon) is not used, the hydrogenation reaction step is avoided, the requirement for equipment is low, normal-pressure reaction operation can be adopted, and the method is suitable for large-scale industrial production.
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- Preparation method of cinacalcet hydrochloride and intermediate thereof
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The invention discloses a preparation method of cinacalcet hydrochloride and an intermediate thereof. The invention provides a preparation method of an intermediate L-cinacalcet tartrate III of cinacalcet hydrochloride. The method comprises the following steps: step (1): in an organic solvent, in the presence of a chiral catalyst and a chiral ligand, an asymmetric hydrogenation reduction reactionis conducted on a cinacalcet intermediate II to obtain cinacalcet IV, wherein the chiral catalyst is bis (1, 5-cyclooctadiene)-rhodium trifluoromethanesulfonate, and the chiral ligand is (S)-3, 3'-bis(2, 4, 6-triisopropylphenyl)-1, 1'-di-2-naphthol cyclic phosphate; and (2) in an organic solvent, a neutralization reaction is conducted between cinacalcet IV and L-tartaric acid to obtain L-cinacalcet tartrate III. The preparation method disclosed by the invention has advantages of short route step, simple and safe operation and high total yield; and the prepared product has high purity, meets the requirements of bulk drugs, is low in production cost and is suitable for industrial production.
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Paragraph 0065-0076
(2020/06/09)
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- Direct synthesis method of chiral secondary amine compound
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The invention relates to a method .for directly synthesizing chiral secondary amine compounds, and the synthesis method. provided by the invention can efficiently obtain the enantioselectivity of the chiral amine compound, under the catalysis of the chiral catalyst of the chiral catalyst, and can achieve 95% .the enantioselectivity of the chiral amine compound in one step by using the synthetic method disclosed by the invention, and has very high industrial application potential, corresponding to the cheap,raw materials.
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Paragraph 0043; 0046
(2020/03/16)
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- Direct N-Alkylation/Fluoroalkylation of Amines Using Carboxylic Acids via Transition-Metal-Free Catalysis
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A scalable protocol of direct N-mono/di-alkyl/fluoroalkylation of primary/secondary amines has been constructed with various carboxylic acids as coupling agents under the catalysis of a simple air-tolerant inorganic salt, K3PO4. Advantageous features include 100 examples, 10 drugs and drug-like amines, fluorinated complex tertiary amines, gram-scale synthesis and isotope-labelling amine, thus demonstrating the potential applicability in industry of this methodology. The involvement of relatively less reactive silicon-hydride compared with the traditional reactive metal-hydride or boron-hydride species required to reduce the amide intermediates presumably contributes to the remarkable functional group compatibility. (Figure presented.).
- Lu, Chunlei,Qiu, Zetian,Xuan, Maojie,Huang, Yan,Lou, Yongjia,Zhu, Yiling,Shen, Hao,Lin, Bo-Lin
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supporting information
p. 4151 - 4158
(2020/08/21)
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- Chemoselective Reductive Aminations in Aqueous Nanoreactors Using Parts per Million Level Pd/C Catalysis
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Condensation in recyclable water between aldehydes or ketones and amines occurs smoothly within the hydrophobic cores of nanomicelles, resulting in imine formation that is subject to subsequent reduction leading, overall, to reductive amination. This micellar technology enables the synthesis of several types of pharmaceuticals, a new procedure that relies on only 2000 ppm (0.20 mol %) palladium from commercially available Pd/C. A broad range of substrates can be used under mild conditions, leading to high chemical yields of the desired secondary and tertiary amines.
- Casotti, Gianluca,Gao, Eugene S.,Jin, Henry S.,Lipshutz, Bruce H.,Takale, Balaram S.,Thakore, Ruchita R.
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supporting information
(2020/09/09)
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- Intermediate and method for preparing cinacalcet hydrochloride
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The invention provides an intermediate compound and a method for preparing cinacalcet hydrochloride. The intermediate compound has a structure represented by formula (I) shown in the description; andX in the formula (I) is selected from Br and Cl. The method for preparing cinacalcet hydrochloride is characterized in that 3-halopropionaldehyde and (R)-1-naphthylethylamine are used as starting compounds, and the cinacalcet hydrochloride is prepared from the intermediate compound of formula (I). The method has the advantages of simplicity, easiness in operation, easily available raw materials, environmental protection, short route, high yield, good purity and easiness in industrial production.
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Paragraph 0042; 0075; 0077; 0078-0079; 0080-0081; 0082-0085
(2019/04/10)
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- A Highly Active PN3 Manganese Pincer Complex Performing N-Alkylation of Amines under Mild Conditions
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A highly active Mn(I) catalyst based on a nonsymmetric PN3-ligand scaffold for the N-alkylation of amines with alcohols utilizing the borrowing hydrogen methodology is reported. A broad range of anilines and the more challenging aliphatic amines were alkylated with primary and secondary alcohols. Moreover, the combination of low catalyst loadings and mild reaction conditions provides high efficiency for this atom-economic transformation.
- Homberg, Leonard,Roller, Alexander,Hultzsch, Kai C.
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supporting information
(2019/05/07)
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- Method for asymmetrically synthesizing (R)-cinacalcet
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The invention discloses a new method for asymmetrically synthesizing (R)-cinacalcet. The method includes: taking racemic 2-bromo-propionic acid (4-methoxybenzyl) ester as a starting raw material, andbeing in asymmetric Negishi cross coupling reaction with 2-nathphyl zinc bromide under catalysis of CoI2 and chiral ligand to generate (R)-2-(1-nathphyl) propionic acid (4-methoxybenzyl) ester; beingin reaction with oxalyl chloride through LiOH reduction to generate (R)-2-(1-nathphyl) propionyl chloride; being reaction with ammonia water to generate (R)-2-(1-nathphyl) propionamide, and allowing Hofmann degradation to obtain (R)-1-nathphalene ethylamine; being in reaction with 3-(trifluoromethyl) phenylpropionic acid to generate (R)-N-(1-nathphalene ethyl)-3-(3-trifluoromethylphenyl) propionamide, and allowing LiAlH4 reduction to obtain (R)-cinacalcet. Cobalt catalyzed asymmetric Negishi cross coupling reaction is utilized for the first time to build the chiral center of (R)-cinacalcet, the method is mild in reaction condition and environment-friendly, and optical purity of (R)-cinacalcet is high (99%ee).
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- PROCESS FOR PRODUCING CINACALCET
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PROBLEM TO BE SOLVED: To provide an industrially usable process for producing cinacalcet that can achieve a high yield by a small number of steps while avoiding generation of impurities without using an unstable source compound. SOLUTION: Provided is a process for producing cinacalcet comprising a step in which protected (R)-1-(1-naphthyl)ethylamine and 3-(3-trifluoromethylphenyl)propanol are reacted using (a) a reagent containing a combination of azodicarboxylic acid ester and phosphine to produce protective group-possessing (R)-N-[1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine. SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
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- Enantioselective synthesis of (R)-Cinacalcet via cobalt-catalysed asymmetric Negishi cross-coupling
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A novel enantioselective synthesis of (R)-cinacalcet with 99% enantiomeric excesses (ee) has been achieved. The main strategies of the approach include a gram-scale cobalt-catalysed asymmetric cross-coupling of racemic ester with arylzinc reagent, Hoffman-type rearrangement of acidamide, the amidation of chiral amine, and improving the ee of chiral amide from 87% to 99% via recrystallization.
- Sun, Xiao,Wang, Xueyang,Liu, Feipeng,Gao, Zidong,Bian, Qinghua,Wang, Min,Zhong, Jiangchun
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p. 682 - 687
(2019/08/07)
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- Cinacalcet hydrochloride preparation method
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The invention provides a cinacalcet hydrochloride preparation method, wherein the cinacalcet hydrochloride finished product is obtained by using 3-(3-trifluoromethylphenyl)propanol and (R)-(+)-1-(1-naphthyl)ethylamine as starting raw materials through two-step chemical reaction, one-step salt formation and two-step purification. According to the present invention, the method has characteristics ofsimple process, easily-available raw materials, economy and environmental protection, easily achieves industrialization, and can promote the economic and technological development of cinacalcet hydrochloride bulk drugs.
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Paragraph 0062-0064
(2019/07/04)
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- B(C6F5)3-Catalyzed Deoxygenative Reduction of Amides to Amines with Ammonia Borane
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The first B(C6F5)3-catalyzed deoxygenative reduction of amides into the corresponding amines with readily accessible and stable ammonia borane (AB) as a reducing agent under mild reaction conditions is reported. This metal-free protocol provides facile access to a wide range of structurally diverse amine products in good to excellent yields, and various functional groups including those that are reduction-sensitive were well tolerated. This new method is also applicable to chiral amide substrates without erosion of the enantiomeric purity. The role of BF3 ? OEt2 co-catalyst in this reaction is to activate the amide carbonyl group via the in situ formation of an amide-boron adduct. (Figure presented.).
- Pan, Yixiao,Luo, Zhenli,Han, Jiahong,Xu, Xin,Chen, Changjun,Zhao, Haoqiang,Xu, Lijin,Fan, Qinghua,Xiao, Jianliang
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supporting information
p. 2301 - 2308
(2019/01/30)
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- Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases
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Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1-acetonaphthone yielded an enantiopure (R)-amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)-alcohol, which was easily converted into the previous (R)-amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co-immobilized on the same porous surface. This self-sufficient heterogeneous biocatalyst presented an accumulated total turnover number (TTN) for the cofactor of 675 after 5 consecutive operational cycles. Finally, in a preparative scale synthesis the TA-based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield. (Figure presented.).
- Marx, Lisa,Ríos-Lombardía, Nicolás,Farnberger, Judith F.,Kroutil, Wolfgang,Benítez-Mateos, Ana I.,López-Gallego, Fernando,Morís, Francisco,González-Sabín, Javier,Berglund, Per
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supporting information
p. 2157 - 2165
(2018/03/05)
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- Iron-Catalyzed Suzuki-Miyaura Cross-Coupling Reactions between Alkyl Halides and Unactivated Arylboronic Esters
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An iron-catalyzed cross-coupling reaction between alkyl halides and arylboronic esters was developed that does not involve activation of the boronic ester with alkyllithium reagents nor requires magnesium additives. A combination of experimental and theoretical investigations revealed that lithium amide bases coupled with iron complexes containing deprotonated cyanobis(oxazoline) ligands were best to obtain high yields (up to 89%) in catalytic cross-coupling reactions. Mechanistic investigations implicate carbon-centered radical intermediates and highlight the critical importance of avoiding conditions that lead to iron aggregates. The new iron-catalyzed Suzuki-Miyaura reaction was applied toward the shortest reported synthesis of the pharmaceutical Cinacalcet.
- Crockett, Michael P.,Tyrol, Chet C.,Wong, Alexander S.,Li, Bo,Byers, Jeffery A.
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supporting information
p. 5233 - 5237
(2018/09/12)
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- Method of preparing N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl) phenyl)-propyl-1-amine hydrochloride
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The invention relates to a method of preparing N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl) phenyl)-propyl-1-amine hydrochloride. Specifically, the method can prepare N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl) phenyl)-propyl-1-amine hydrochloride (I) through simple substitution and refining and salifying by taking a compound (II) as an initial raw material. The synthetic route hasthe advantages of being simple to operate, environment-friendly, good in yield, high in optical purity of obtained products, easy for industrial production and the like. The formula is as shown in thedescription.
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Paragraph 0085; 0086; 0087
(2018/04/26)
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- B(C6F5)3-Catalyzed Asymmetric Reductive Amination of Ketones with Ammonia Borane
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The first example of metal-free B(C6F5)3-catalyzed asymmetric reduction amination of ketones with chiral α-methylbenzylamine (α-MBA) using ammonia borane as the reductant is reported. This one-pot method has a broad substrate scope and provides various chiral amines in 81-95% yield with 80-99% de. This protocol was further applied in the total synthesis of cinacalcet.
- Pan, Zhentao,Shen, Leixin,Song, Dingguo,Xie, Zhen,Ling, Fei,Zhong, Weihui
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p. 11502 - 11509
(2018/09/25)
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- Hydrochloric cinacalcet preparation method
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The invention discloses a hydrochloric cinacalcet preparation method. Commercial m-(trifluoromethyl) acetophenone, formaldehyde, (R)-1-(1-naphthyl) ethylamine and the like serve as raw materials, an intermediate (R)-3-(1-(naphthalene-1-base) ethyl amino)-1-(3-(trifluoromethyl) phenyl) propane-1-ketone is prepared by multi-component Mannich reaction and subjected to reduction reaction to prepare cinacalcet, and the cinacalcet reacts with hydrochloric acid, so that hydrochloric cinacalcet can be prepared. The preparation method is short in synthetic route, low in raw material cost, low in price, safe in normal pressure reaction operation and suitable for large-scale production and has good social and economic benefits, and metal zinc amalgam reducing agents are used. Experiments prove that the recrystallization yield of the cinacalcet can reach 93.4% or more, the purity of the cinacalcet can reach 99.6% or more, the yield of the hydrochloric cinacalcet can reach 94.2% or more, and the purity of the hydrochloric cinacalcet can reach 99.7% or more.
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- Method for preparing cinacalcet hydrochloride
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The invention discloses a method for preparing cinacalcet hydrochloride and belongs to the field of synthesis and preparation of chemical drugs. The method disclosed by the invention comprises the following steps: taking bromo-alpha,alpha,alpha-trifluorotoluene (II) and acryloyl chloride (III) as raw materials, and preparing m-trifluoromethyl acrylketone (IV) through a coupled reaction; carrying out an addition reaction between (IV) and (R)-1-(1-naphthyl) ethamine (V) so as to generate (R)-3-(1-(1-naphthyl)ethylamino)-1-(3-trifluoromethyl)phenyl)-1-acetone (VI); reducing (VI) to prepare N-((1R)-1-(1-naphthyl)ethyl)-3-(3-trifluoromethyl)phenyl)-1-propylamine (cinacalcet) (VII); carrying out a salt forming reaction on cinacalcet, thereby obtaining N-((1R)-1-(1-naphthyl)ethyl)-3-(3-trifluoromethyl)phenyl)-1-propylamine hydrochloride, namely the cinacalcet hydrochloride (I). According to the route, the cheap and readily available bromo-alpha,alpha,alpha-trifluorotoluene (II) and acryloyl chloride (III) are taken as the raw materials, a few steps are needed, usage of compounds of a heavy metal Pd and metal reducing agents LiAlH4, NaBH4 and the like is avoided, and the method is safe, environmentally friendly and economic and is suitable for large-scale industrial production.
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Paragraph 0026; 0036; 0037; 0044; 0051
(2017/08/30)
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- Method for synthesizing cinacalcet hydrochloride
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The invention provides a method for synthesizing cinacalcet hydrochloride. The method comprises the following steps: protecting an R-naphthyl ethylamine raw material by virtue of o-nitro benzenesulfonyl chloride, so as to obtain an intermediate XN-3; forming ester by m-trifluoromethyl phenylpropanol and methyl benzene sulfonyl chloride, so as to obtain an intermediate XN-4; refluxing the XN-3 and the XN-4 for 1-2 hours in methylbenzene, so as to obtain an intermediate XN-5; removing a protecting group under the action of mercaptoacetic acid to obtain an intermediate XN-6; and salifying in hydrochloric acid, so as to obtain the target compound. The synthetic route is applicable to industrialized enlarged production and has the characteristics of simple operation, no potential safety hazard, high yield and the like.
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- A synthesis method of the west that card plug
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The invention provides a method for synthesizing cinacalcet. According to the method, (R)-1-(1-naphthyl)ethylamine and 3-(3-trifluoromethylphenyl)propionic acid are adopted as raw materials; a nonmetal boron compound is adopted as a catalyst; an organosilane compound is adopted as a reducing agent; and a target product is synthesized with one step through a reductive coupling process. The method provided by the invention is simple and is easy to operate; and the raw materials are easy to obtain, such that cost is low. Also, no metal catalyst is needed in the synthesis process, such that metal residue in the drug is avoided, and the method is safe and environment-friendly. The method meets the requirements of green chemistry.
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Paragraph 0053-0058; 0060; 0061; 0063; 0064; 0066-0088
(2017/06/27)
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- A method for synthesizing [...]
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The invention discloses a synthesis method of cinacalcet. The synthetic route is divided into two parts, namely, (1) preparing a chiral compound as shown in the description from racemic 1-naphthylethylamine as a starting material by virtue of a dynamic kinetic reliquid method in the presence of Pd/LDH-SA serving as a racemic catalyst, p-chlorophenol fatty acyl ester serving as an acyl donor and lipase serving as a biological reliquid catalyst; and (2) reacting m-trifluoromethylbenzaldehyde serving as a starting material and a cheap and easily available material acetaldehyde to obtain m-trifluoromethyl cinnamic aldehyde and carrying out reduced pressure distillation to obtain a pure product; reacting m-trifluoromethyl cinnamic aldehyde and the compound as shown in the description to produce an imine intermediate; dissolving the imine intermediate in ethanol and reacting in the presence of Raney nickel serving as a hydrogenation catalyst to obtain the product cinacalcet. By the synthesis method, the reaction yield and the optical purity of the product are increased, the reaction conditions are milder and the raw materials are easily available.
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Paragraph 0044
(2016/11/21)
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- Hydrochloric acid and intermediates [...] the synthetic method of the compound of
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The invention provides a synthetic method of cinacalcet hydrochloride intermediate compound meta-trifluoro methyl phenylpropyl bromine and cinacalcet hydrochloride. According to the synthetic method, synthetic technology of intermediate compound meta-trifluoro methyl phenylpropyl bromine is optimized, so that yield and purity of meta-trifluoro methyl phenylpropyl bromine and cinacalcet hydrochloride are improved significantly, product quality is ensured, raw material utilization ratio is increased, and product cost is reduced effectively.
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- Design of modified amine transfer reagents allows the synthesis of α-chiral secondary amines via CuH-catalyzed hydroamination
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The CuH-catalyzed hydroamination of alkenes and alkynes using a silane and an amine transfer reagent represents a simple strategy to access chiral amine products. We have recently reported methods to prepare chiral amines with high efficiency and stereoselectivity using this approach. However, the current technology is limited to the synthesis of trialkylamines from dialkylamine transfer reagents (R2NOBz). When monoalkylamine transfer reagents [RN(H)OBz] were used for the synthesis of chiral secondary amines, competitive, nonproductive consumption of these reagents by the CuH species resulted in poor yields. In this paper, we report the design of a modified type of amine transfer reagent that addresses this limitation. This effort has enabled us to develop a CuH-catalyzed synthesis of chiral secondary amines using a variety of amine coupling partners, including those derived from amino acid esters, carbohydrates, and steroids. Mechanistic investigations indicated that the modified amine transfer reagents are less susceptible to direct reaction with CuH.
- Niu, Dawen,Buchwald, Stephen L.
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supporting information
p. 9716 - 9721
(2015/08/18)
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- 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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Abstract A 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.
- Gooodman, Cassie A.,Janci, Elise Marie,Onwodi, Olivia,Simpson, Chad C.,Hamaker, Christopher G.,Hitchcock, Shawn R.
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supporting information
p. 4468 - 4471
(2015/06/30)
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- Boron-Catalyzed N-Alkylation of Amines using Carboxylic Acids
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A boron-based catalyst was found to catalyze the straightforward alkylation of amines with readily available carboxylic acids in the presence of silane as the reducing agent. Various types of primary and secondary amines can be smoothly alkylated with good selectivity and good functional-group compatibility. This metal-free amine alkylation was successfully applied to the synthesis of three commercial medicinal compounds, Butenafine, Cinacalcet. and Piribedil, in a one-pot manner without using any metal catalysts.
- Fu, Ming-Chen,Shang, Rui,Cheng, Wan-Min,Fu, Yao
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supporting information
p. 9042 - 9046
(2015/08/03)
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- Oligomer and related compd. [...] -
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The invention relates to (among other things) oligomer-calcimimetic conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over previously administered compounds.
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Paragraph 0167-0169
(2016/11/07)
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- Metal-free catalytic hydrogenation of imines with recyclable [2.2]paracyclophane-derived frustrated lewis pairs catalysts
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A series of [2.2]paracyclophane-derived frustrated Lewis pairs (FLPs) with reversible, metal-free hydrogen activation was synthesized and successfully applied in the hydrogenation of imines in moderate to good yields. The high stability of the novel FLP system enables effective recycling of the metal-free catalysts. This reaction could also be compatible with a larger scale and developed into a pharmaceutical synthesis of cinacalcet {(R)-N-[1-(1-naphthyl) ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine} without heavy metal residues.
- Wang, Guan,Chen, Cheng,Du, Tieqi,Zhong, Weihui
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p. 1747 - 1752
(2014/06/09)
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- AN IMPROVED PROCESS FOR PREPARATION OF N-[1-(1-NAPHTHYL)ETHYL] -3- [3-(TRIFLUOROMETHYL)PHENYL]PROPAN-1-AMINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to an improved process for preparation of N- [1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine and pharmaceutically acceptable salts thereof. In particular, the present invention relates to an improved process for preparation cinacalcet or pharmaceutically acceptable salts and intermediates thereof.
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- PROCESSES FOR THE PREPARATION OF CINACALCET
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The present invention provides processes and intermediates for preparing cinacalcet base and pharmaceutically acceptable salts thereof.
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Page/Page column 11; 13
(2012/12/14)
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- Synthesis of amines from alcohols in a nonepimerizing one-pot sequence - Synthesis of bioactive compounds: Cinacalcet and dexoxadrol
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A general, mild, and chemoselective one-pot oxidation/imine-iminium formation/nucleophilic addition sequence allowing the N-alkylation of amines by alcohols is described. This metal-free, one-pot sequence produced a wide variety of amines in good yields and diastereoselectivities, without the epimerization of the enantioenriched amines or alcohols involved in the process. This method was applied to the syntheses of the biologically active compounds cinacalcet and dexoxadrol. Copyright
- Guerin, Claire,Bellosta, Veronique,Guillamot, Gerard,Cossy, Janine
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experimental part
p. 2990 - 3000
(2012/07/13)
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- Iron triflate catalyzed reductive amination of aldehydes using sodium borohydride
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An efficient and convenient procedure for the reductive amination of aldehydes using NaBH4 in the presence of catalytic amount of Fe(OTf)3 is described.
- Uday Kumar,Sudhakar Reddy,Prabhakar Reddy,Bandichhor, Rakeshwar
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supporting information; experimental part
p. 4354 - 4356
(2012/10/08)
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- PROCESS FOR PREPARING CINACALCET AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The resent invention rovides a novel rocess for re arin cinacalcet of formula I and pharmaceutically acceptable salts thereof and process of purification. The present invention also provides novel nitrogen protected synthetic intermediates useful in the process of the present invention. Further, the present invention provides a novel substituted carbamate impurity and process of preparation thereof.
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Page/Page column 21
(2011/08/03)
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- Method For The Preparation Of Cinacalcet And Intermediates And Impurities Thereof
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A method for the preparation of Cinacalcet is disclosed comprising treating (R)-1-naphthyl ethylamine with an aromatic aldehyde to form (1R)-1-(2-naphthyl)-N-(aryl methylene)ethanamine derivative of Formula (IV), which is further treated with 1-(3-halopropyl)-3-(trifluoromethyl)benzene of Formula (V) to obtain an iminium salt of Formula (VI), followed by hydrolysis to obtain Cinacalcet free base.
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Page/Page column 17
(2012/01/13)
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- PROCESS FOR THE PREPARATION OF CINACALCET AND INTERMEDIATES THEREOF
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The present invention relates to a process for the preparation of (R)-(1-Naphthalen-1-yl-ethyl)-[3-(3-trifluoromethyl-phenyl)-propyl]-amine or a salt thereof, in particular the hydrochloride, and intermediates useful in its synthesis.
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Page/Page column 4
(2011/06/19)
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- A process for the preparation of cinacalcet and intermediates thereof
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The present invention relates to a process for the preparation of (R)-(1-Naphthalen-1-yl-ethyl)-[3-(3-trifluoromethyl-phenyl)-propyl]-amine or a salt thereof, in particular the hydrochloride, and intermediates useful in its synthesis.
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- An investigation into the one-pot Heck olefination-hydrogenation reaction
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Herein is described an operationally simple process concerning the observation that, following either inter-, or intramolecular Heck olefination, stirring of the so formed substituted alkenyl product under an atmosphere of hydrogen efficiently effects alkene hydrogenation. Overall this two-operation, one-pot "reductive Heck" sequence is notable since direct reductive Heck processes, using additives such as formate salts, are restricted to a limited range of substrates. In total 25 examples are reported (yields ranging from 0 to 95%), which were selected in order to probe the scope and limitations of this method. Finally, the utility of this sequence was demonstrated in a short synthesis of the calcimimetic agent, cinacalcet.
- Geoghegan, Kimberly,Kelleher, Susan,Evans, Paul
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p. 2187 - 2194
(2011/05/14)
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- HIGHLY PURE CINACALCET OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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Provided herein are impurities of cinacalcet, (R)-α-methyl-N-[3-[3-(trifluoromethyl) phenyl]propyl]-1-(5,6,7,8-tetrahydronaphthalene)methaneamine (tetrahydro cinacalcet impurity), (R)-α-Methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1- naphthalenemethaneamine-N-oxide (cinacalcet N-oxide impurity) and (R)-α-methyl-N-[3-[3- (trifiuoromethyl)phenyl]methyl]-1-naphthalenemethaneamine (benzylamine impurity); and processes for preparation and isolation thereof. Provided further herein is a highly pure cinacalcet or a pharmaceutically acceptable salt thereof substantially free of impurities, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure cinacalcet or a pharmaceutically acceptable salt thereof substantially free of impurities.
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Page/Page column 42
(2010/07/02)
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- PROCESS FOR PREPARING CINACALCET AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The resent invention rovides a novel rocess for re arin cinacalcet of formula I and pharmaceutically acceptable salts thereof and process of purification. The present invention also provides novel nitrogen protected synthetic intermediates useful in the process of the present invention. Further, the present invention provides a novel substituted carbamate impurity and process of preparation thereof.
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Page/Page column 43-44
(2010/04/03)
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- A NEW METHOD FOR THE PREPARATION OF CINACALCET AND NEW INTERMEDIATES THEREOF
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A new method for the preparation of Cinacalcet by treating (R)-1-naphthyl ethylamine with an aromatic aldehyde to form (1R)-1-(2-naphthyl)-N-(aryl methylene)ethanamine derivative which is further treated with 1 -(3-hdopropyl)-3-(triflupromethyl) benzene of formula (V) to obtain an iminium salt and followed by hydrolysis to obtain Cinacalcet free base. A new compound, (1R)- I-(2-naphthyl)-N-(aryhnethylene)ethanamine, of formula (IV) and an iminium salt compound of formula (VI) are disclosed. which are intermediates for the preparation of Cinacalcet.
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Page/Page column 18
(2010/10/03)
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- PROCESS FOR THE PREPARATION OF CINACALCET AND SALTS THEREOF, AND INTERMEDIATES FOR USE IN THE PROCESS
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There is provided a process for preparing a salt of the (R)- or (S)-isomer of 1- naphthylethylamine with mandelic acid or a derivative thereof, the process comprising reacting racemic 1-naphthylethylamine with mandelic acid or a derivative thereof to obtain the (R)- or (S)-isomer of 1-naphthylethylamine salt (III) with the acid. The salts also form an aspect of the present invention. There is also provided a salt of the (R)- or (S)-isomer of 1-naphthylethylamine with mandelic acid or a derivative thereof. There is also provided a process for preparing cinacalcet (I) or a salt thereof, the process comprising reacting an ester (II) with (R)-i-naphthylethylamine or a salt of (R)-i-naphthylethylamine and mandelic acid or a derivative thereof, to obtain cinacalcet, and optionally converting the cincalcet to a salt thereof.
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Page/Page column 20-21
(2010/09/18)
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- PROCESS FOR PREPARING CINACALCET
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A process for preparing N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)-phenyl]propan-1-amine of formula (I) i.e. Cinacalcet and its intermediates of formulae (V), (Va) and (Vb).
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Page/Page column 28
(2010/05/14)
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- A PROCESS FOR THE PREPARATION OF CINACALCET AND ITS SALTS
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A process for preparing (cinacalcet) α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine (formula I): or a pharmaceutically acceptable salt thereof which comprises: a) reacting 1-acetonaphthone with an alkyl amine or a substituted or non-substituted aralkyl amine in presence of a suitable solvent to form imine compound (formula III), which on reduction using suitable reducing agent yields N-substituted naphthyl ethyl amine (formula IV). b) Optionally resolving the N-substituted naphthyl ethyl amine (formula (IV) into its corresponding (R) or (S) isomer (formula IVa and IVb). c) Further reacting the (R,S) or (R) or (S)-N-substituted naphthyl ethyl amine (formula IV, IVa, or IVb) with trifluoromethyl aryl alkyl compound (formula V) in presence of a base and in a suitable solvent to form an intermediate corresponding to (R5S), (R) or (S)-N-substituted- methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (N-substituted- cinacalcet) (formula VI, Via or VIb). d) Optionally resolving (R,S)-N-substituted cinacalcet (formula VI) into its corresponding (R) and (S) isomers (formula Via or VIb). e) Converting (R5S) or (R) or (S)-N-substituted-cinacalcet (formula VI, Via or VIb) to the corresponding (R5S) or (R) or (S)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine (cinacalcet) (formula, I5 Ia or Ib)) by dealkylation or debenzylation, f) Optionally resolving (R,S)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-l- naphthalenemethanamine (cincacalcet, formula I) into (R) and (S)-α-methyl-N-[3-[3- (trifluoromethyl)phenyl]propyl]-l-naphthalenemethanamine (formula Ia and Ib) using a suitable resolving agent.
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Page/Page column 18-19
(2010/04/03)
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