- Creating High Regioselectivity by Electronic Metal-Support Interaction of a Single-Atomic-Site Catalyst
-
Ligands are the most commonly used means to control the regioselectivity of organic reactions. It is very important to develop new regioselective control methods for organic synthesis. In this study, we designed and synthesized a single-atomic-site catalyst (SAC), namely, Cu1-TiC, with strong electronic metal-support interaction (EMSI) effects by studying various reaction mechanisms. π cloud back-donation to the alkyne on the metal catalytic intermediate was enhanced during the reaction by using transient electron-rich characteristics. In this way, the reaction achieved highly linear-E-type regioselective conversion of electronically unbiased alkynes and completely avoided the formation of branched isomers (ln:br >100:1, TON up to 612, 3 times higher than previously recorded). The structural elements of the SACs were designed following the requirements of the synthesis mechanism. Every element in the catalyst played an important role in the synthesis mechanism. This demonstrated that the EMSI, which is normally thought to be responsible for the improvement in catalytic efficiency and durability in heterogeneous catalysis, now first shows exciting potential for regulating the regioselectivity in homogeneous catalysis.
- Jing, Hongyu,Li, Jiong,Li, Wen-Hao,Li, Yadong,Wang, Dingsheng,Wang, Yu,Yang, Jiarui,Zhang, Jian,Zhao, Jie
-
p. 15453 - 15461
(2021/09/30)
-
- Preparation method of cinacalcet hydrochloride
-
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.
- -
-
-
- Cinacalcet intermediate and synthesis method of cinacalcet hydrochloride
-
The invention relates to a cinacalcet intermediate and a synthesis method of cinacalcet hydrochloride. The synthesis method of cinacalcet hydrochloride comprises the steps of (c) in an organic solvent, carrying out olefin metathesis reaction on a compound N-III and a compound B-2 under the action of a catalyst to obtain a compound C-I; (d) carrying out hydrogenation reduction reaction on the compound C-I to obtain a compound C-II; and (e) removing an amino protecting group from the compound C-II, and salifying with hydrogen chloride to obtain cinacalcet hydrochloride. The method has the advantages of high yield, high chemical purity and optical purity of the product, simple post-treatment process, simple and easily available raw materials, and facilitation of industrial production. The reaction formula is shown in the description, wherein R is selected from t-butyloxycarbonyl, benzoyl and carbobenzoxy.
- -
-
Paragraph 0155; 0158; 0171-0173
(2021/07/17)
-
- Preparation method of cinacalcet hydrochloride and intermediate thereof
-
The invention discloses a preparation method of cinacalcet hydrochloride and an intermediate thereof. The invention provides a cinacalcet II preparation method, which comprises: in a solvent, carrying out a reduction reaction on 3-(3-trifluoromethyl-phenyl)-N-(R)-(1-naphthyl-1-ethyl)-propanamide and a reducing agent, and after the reaction is completed, carrying out a quenching reaction by using a metal sulfate hydrate to obtain cinacalcet II, wherein the reducing agent is an alkali metal hydroboron and boron trifluoride system; the structural general formula of the hydrated sulfuric acid metal salt is Mx(SO4)y.zH2O, M is one or more of metal ions and ammonium radicals of a first period, a second period, a third period and a fourth period in a periodic table of elements, x is 1-2, y is 1-3, and z is 0-20. The preparation method is simple, high in safety, low in equipment requirement and suitable for industrial production, and the prepared cinacalcet hydrochloride product is high in purity and yield.
- -
-
Paragraph 0054-0069
(2021/05/05)
-
- Preparation method of cinacalcet hydrochloride
-
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.
- -
-
-
- Preparation method of cinacalcet hydrochloride
-
The invention provides a preparation method of cinacalcet hydrochloride, which comprises the following steps: (1) reacting a compound as shown in a formula I with thionyl chloride under the conditionsthat isopropyl acetate and N, N-dimethylformamide are used as solvents and the temperature is 40-45 DEG C to obtain a product; (2) directly reacting the product obtained in the step (1) with a raw material A to obtain an intermediate I; and (3) carrying out reduction reaction and refining on the intermediate I obtained in the step (2) to obtain cinacalcet hydrochloride. According to the preparation method provided by the invention, by using isopropyl acetate and N, N-dimethylformamide (DMF) as solvents in the first-step reaction, compared with the prior art requiring the reaction conditions of higher reaction temperature and a large amount of thionyl chloride, the temperature is greatly reduced, the use amount of thionyl chloride is reduced, higher yield is still ensured, and the method has higher industrialization value.
- -
-
Paragraph 0036-0041
(2020/10/05)
-
- Preparation method of cinacalcet hydrochloride and intermediate thereof
-
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.
- -
-
Paragraph 0086-0088
(2020/06/09)
-
- PROCESS FOR PRODUCING CINACALCET
-
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
- -
-
-
- Synthesis method of high-purity cinacalcet hydrochloride
-
The invention relates to a synthesis method of high-purity cinacalcet hydrochloride. The cinacalcet hydrochloride is prepared from amide as shown in a formula IV by carrying out a reduction reaction in a reducing agent, a catalyst and a solvent, carrying out hydrolysis, and then, forming a salt by using a hydrochloric acid, wherein the solubility of the reducing agent in the used solvent at a reaction temperature is not larger than 2.0 g/100 ml. The synthesis processes are as follows. The synthesis method of high-purity cinacalcet hydrochloride has the advantages that the high-purity cinacalcet hydrochloride is obtained after a reaction realized by selecting a reasonable combination of the reducing agent and the solvent and controlling the solubility of the selected reducing agent in the used solvent not to be larger than 2.0 g/100 ml, the content of impurities as shown in a formula II and a formula III in a product can be greatly reduced and even cannot be detected.
- -
-
Paragraph 0048-0076
(2019/11/20)
-
- Cinacalcet hydrochloride preparation method
-
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.
- -
-
Paragraph 0065-0073
(2019/07/04)
-
- Chemical-enzyme method used for synthesis of cinacalcet
-
The invention discloses a chemical-enzyme method used for synthesis of cinacalcet. The chemical-enzyme method cmprises following steps: under catalyst effect of lipase, racemic 1-(1-naphthyl)ethanol and a fatty acid vinyl ester are subjected to kinetic resolution in a solvent so as to obtain (S)-1-(1-naphthyl) ethanol; under the effect of a catalyst, (S)-1-(1-naphthyl) ethanol and 3-(3-(trifluoromethyl)phenyl)propylamine are subjected to Mitsunobu reaction so as to obtain cinacalcet. According to the chemical-enzyme method, racemic 1-(1-naphthyl)ethanol is taken as an initial raw material, biological enzyme resolution is adopted so as to obtain (S)-1-(1-naphthyl) ethanol, and (S)-1-(1-naphthyl) ethanol and 3-(3-(trifluoromethyl)phenyl)propylamine are subjected to Mitsunobu reaction so asto obtain cinacalcet. Compared with the prior art, the advantages are that: reaction steps are few; operation is simple; no high pressure container is used for hydrogenation reduction; no expensive reducing agent is used; reaction conditions are mild; safety is high; the yield and purity are high; and the purity is as high as 99% or higher.
- -
-
Paragraph 0041; 0042; 0048; 0051; 0054; 0057
(2019/01/22)
-
- Method of preparing N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl) phenyl)-propyl-1-amine hydrochloride
-
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.
- -
-
Paragraph 0075; 0078; 0079; 0083; 0084; 0088; 0089
(2018/04/26)
-
- High-purity hydrochloric acid of [...] preparation method
-
The invention discloses a preparation method of high-purity cinacalcet hydrochloride. The preparation method of the high-purity cinacalcet hydrochloride comprises the following steps: performing an alkylation reaction of 3-(3-(trifluoromethyl)phenyl) propyl ester with (R)-1-(naphthyl-1-yl) ethylamine salt in the presence of a solvent and an acid-binding agent, and performing salt forming to obtain the cinacalcet hydrochloride with the purity of more than or equal to 99.5%. The (R)-1-(naphthyl-1-yl) ethylamine salt is (R)-1-(naphthyl-1-yl) ethylamine hydrochloride or (R)-1-(naphthyl-1-yl) ethylamine sulphate, the solvent is a mixed solvent of water and an aprotic organic solvent, and the aprotic organic solvent is methylbenzene or dimethylbenzene. The volume of water is 5-90% of that of the aprotic organic solvent, the weight of the aprotic organic solvent is 1-10 times that of the 3-(3-(trifluoromethyl) phenyl) propyl ester. The high-purity cinacalcet hydrochloride with the purity of more than or equal to 99.5% can be finally obtained according to the method disclosed by the invention. The method is simple in operation and applicable to the industry.
- -
-
Paragraph 0020-0023
(2018/05/24)
-
- Method for preparing cinacalcet hydrochloride
-
The invention provides a method for preparing cinacalcet hydrochloride. The method comprises the following steps: with 3-(3-trifluoromethylphenyl)propanol shown as a formula I as a starting material,performing an acylation reaction on the starting material and methylsulfonyl chloride to obtain methylsulfonyl-3-(3-trifluoromethylphenyl) propyl ester shown as a formula II; in the presence of K2CO3,KI and ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate, performing a substitution reaction on the methylsulfonyl-3-(3-trifluoromethylphenyl) propyl ester shown as the formula II and (R)-1-(1-naphthyl)ethylamine shown as a formula III to obtain a system containing a compound shown as a formula IV; performing a salt forming reaction on the compound shown as the formula IV and hydrochloric acid to obtain a target product, namely the cinacalcet hydrochloride. Through the addition of the trace KI and the ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate in the substitution reaction in the step 2), the substitution reaction is speeded up, the yield of the product is increased and the purity of the product is improved.
- -
-
Paragraph 0037-0044; 0047-0055
(2019/01/14)
-
- Method for synthesizing calcimimetic cinacalcet hydrochloride
-
The invention provides a method for synthesizing calcimimetic cinacalcet hydrochloride; the method comprises the steps of preparing methylsulfonyl-3-(3-trifluoromethylphenyl)propionate; preparing (R)-(+)-1-(1-naphthyl)ethyltribenzyllamine; preparing N-((1R)-1-(1-napthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propyl-1-tribenzylamine; preparing N-((1R)-1-(1-napthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propylamine hydrochloride. The synthetic route of the method has the advantages of low price and easy access of materials, good operational simplicity, high yield and the like.
- -
-
-
- Method for synthesizing cinacalcet hydrochloride
-
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.
- -
-
-
- Hydrochloric acid [...] and its intermediate synthesis method
-
The invention discloses a synthesis method of cinacalcet hydrochloride and an intermediate thereof. The cinacalcet hydrochloride is prepared by carrying out asymmetric reduction ammonification on 3-(3-(trifluoromethyl)phenyl)propyl-1-amine and 1-(naphthyl-1-yl)ethyl ketone. The asymmetric reduction ammonification is performed by carrying out asymmetric induction by combining a Hantzsch ester and a chiral phosphine ligand. The 3-(3-(trifluoromethyl)phenyl)propyl-1-amine is prepared by the following steps: carrying out Heck coupling reaction on 3-bromo-1-trifluoromethyl benzene and acrylonitrile to obtain 3-(3-(trifluoromethyl)phenyl)acrylonitrile, and carrying out catalytic hydrogenation. The catalyst of the Heck coupling reaction is tetra(triphenylphosphine) palladium, DBA palladium or palladium acetate. The method for synthesizing cinacalcet hydrochloride greatly lowers the production cost, and is suitable for industrialized mass production. The method for synthesizing the 3-(3-(trifluoromethyl)phenyl)propyl-1-amine greatly lowers the production cost, and has higher yield.
- -
-
-
- Method for preparing cinacalcet hydrochloride
-
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.
- -
-
-
- PROCESS FOR PREPARATION OF CINACALCET INTERMEDIATE AND CINACALCET HYDROCHLORIDE
-
The present invention provides one pot process for preparation of highly pure unsaturated cinacalcet hydrochloride (II) comprising: i) converting 3-(trifluromethyl) cinnamic acid (III) into 3-(3-(trifluoromethyl)phenyl)prop-2-en-1-ol (IV), ii) converting 3-(3-(trifluoromethyl)phenyl)prop-2-en-1-ol (IV) to compound (V), wherein R is Cl, Br, I, tosylate and mesylate, Formula (V) iii) reacting compound (V) with (R)-1-(1-Naphthyl) ethylamine (VI) in presence of base followed by treatment with hydrochloric acid. The present invention further provides conversion of unsaturated cinacalcet hydrochloride (II) to cinacalcet hydrochloride (I).
- -
-
Page/Page column 7
(2016/12/22)
-
- A hydrochloride [...] synthesis and refining method
-
The invention explores a method for synthesizing and refining cinacalcet hydrochlorid, especially avoids toxic and expensive reaction reagents reported in literatures; the invention has the advantages of convenient sources of raw materials and reagents, low cost, little pollution to environment and simple operation, the invention is suitable for industrial production.
- -
-
Paragraph 0039; 0049-0052
(2017/02/09)
-
- Hydrochloric acid and intermediates [...] the synthetic method of the compound of
-
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.
- -
-
Paragraph 0048; 0052; 0053; 0054; 0055; 0056
(2016/10/10)
-
- Process for Preparing Cinacalcet and Pharmaceutically Acceptable Salts Thereof
-
The present patent application relates to a process for preparing, cinacalcet or a pharmaceutically acceptable salt thereof, which comprises reacting 3-trifluoromethylbenzaldehyde having the following formula (II) with the phosphorus-comprising derivative having the following formula all) in which R1 and R2, which may he identical or different, are each a (C1-C6)alkyl group. The present invention also relates to the phosphorus-comprising derivative having the formula (III), to the use thereof and to the process for preparing same. The present invention also relates to the phosphate salt of cinacalcet and to uses thereof.
- -
-
Paragraph 0116-0117
(2015/10/05)
-
- PROCESS FOR PREPARING CINACALCET HYDROCHLORIDE
-
Method for preparing cinacalcet hydrochloride having the steps of heating (R)-1-naphthyl ethylamine (Formula I) and 3-(trifluoromethyl)benzene (Formula II) wherein L is a halogen atom, methanesulfonate group (OMs), p-Toluenesulfonate (OTs), or triflate (OTf), in an organic solvent in presence of an inorganic base, refluxing until 3-(trifluoromethyl)benzene is completely consumed, obtaining a reaction mixture containing cinacalcet, and after treatment, obtaining cinacalcet hydrochloride having a formula of The post treatment separates (R)-1-naphthyl ethylamine hydrochloride and cinacalcet hydrochloride by adjusting pH value, extraction, and other simple operations, and the (R)-1-naphthyl ethylamine obtained is recycled for preparing the next batch of cinacalcet hydrochloride.
- -
-
Paragraph 0034-0035
(2015/03/28)
-
- Construction of 3-arylpropylamines using Heck arylations. the total synthesis of cinacalcet hydrochloride, alverine, and tolpropamine
-
New synthetic routes toward the commercial drugs cinacalcet hydrochloride, alverine, and tolpropamine were developed using a Heck-Matsuda arylation as the key-step. Several reaction conditions were evaluated for the Heck-Matsuda reaction using allylamine derivatives and arenediazonium salts. For cinacalcet hydrochloride, N-formylamide provided the best result, furnishing the synthetic target in a very high overall yield (75% over five steps). For alverine, the best results were obtained using a double Heck-Matsuda strategy, providing alverine in an excellent overall yield (69%) from N-acetyl diallylamine in three steps. Tolpropamine was synthesized in a 46% yield over five steps using an efficient reductive Heck-Matsuda arylation between p-bromo-methylcinnamate with 3-chloro tolyldiazonium salt, generating the ,diaryl propionate that was converted to tolpropamine.
- Prediger, Patrícia,Da Silva, Allan Ribeiro,Correia, Carlos Roque Duarte
-
p. 3333 - 3341
(2014/05/06)
-
- AN IMPROVED PROCESS FOR PREPARATION OF N-[1-(1-NAPHTHYL)ETHYL] -3- [3-(TRIFLUOROMETHYL)PHENYL]PROPAN-1-AMINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
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.
- -
-
Page/Page column 21
(2014/11/13)
-
- Direct catalytic N-alkylation of amines with carboxylic acids
-
A straightforward process for the N-alkylation of amines has been developed applying readily available carboxylic acids and silanes as the hydride source. Complementary to known reductive aminations, effective C-N bond construction proceeds under mild conditions and allows obtaining a broad range of alkylated secondary and tertiary amines, including fluoroalkyl-substituted anilines as well as the bioactive compound Cinacalcet HCl.
- Sorribes, Iván,Junge, Kathrin,Beller, Matthias
-
p. 14314 - 14319
(2014/12/10)
-
- Direct reductive alkylation of amine hydrochlorides with aldehyde bisulfite adducts
-
A mild procedure for the direct reaction of aromatic and aliphatic aldehyde bisulfite adducts with primary and secondary amine hydrochlorides in the presence of sodium cyanoborohydride in methanol is reported.
- Barniol-Xicota, Marta,Turcu, Andreea L.,Codony, Sandra,Escolano, Carmen,Vázquez, Santiago
-
supporting information
p. 2548 - 2550
(2014/05/06)
-
- A PROCESS FOR THE PREPARATION OF CINACALCET HYDROCHLORIDE AND ITS INTERMEDIATE
-
This invention relates to a process for the preparation of cinacalcet hydrochloride and its key intermediate 3-[3-(trifluoromethyl) phenyl]propionaldehyde, said process comprising reductive amination of 3-[3-(trifluoromethyl)phenyl]propionaldehyde and (R)-(1-napthylethylamine) in presence of activated sodium borohydride by an acid; the invention also provides a process for preparing 3- [3-(trifluoromethyl)phenyl]propionaldehyde by reacting 3-[3- (trifluoromethyl)phenyl]propan-1-ol (IV) with dimethylsulfide and N-chlorosuccinamide; or dimethylsulfide and N-bromosuccinamide; or dimethylsulfide and chlorine gas; or thioanisole and N-chlorosuccinamide; or thioanisole and N-bromosuccinamide in a suitable organic solvent.
- -
-
Page/Page column 5; 9
(2014/02/16)
-
- A practical procedure for reduction of primary, secondary and tertiary amides to amines
-
A mild and general procedure for reduction of primary, secondary, and tertiary amides using catalytic triruthenium dodecacarbonyl and 1,1,3,3-tetramethyldisiloxane as reductant is described. The reaction is tolerant of numerous functional groups, and the amine products can often be isolated by direct crystallization as hydrochloride salts. The catalyst and silane are commercially available, air stable, and inexpensive, making the procedure accessible for both laboratory and large-scale applications. Copyright
- Reeves, Jonathan T.,Tan, Zhulin,Marsini, Maurice A.,Han, Zhengxu S.,Xu, Yibo,Reeves, Diana C.,Lee, Heewon,Lu, Bruce Z.,Senanayake, Chris H.
-
supporting information
p. 47 - 52
(2013/03/13)
-
- A METHOD OF PRODUCING CINACALCET
-
A new efficient method of producing Cinacalcet of formula I and its pharmaceutically acceptable salts, which consists in direct alkylation of (R)-(1-naphthyl)ethylamine of formula III with 3-[3-(trifluoromethyl)phenyl]propanol of formula II in presence of a catalyst in an inert organic solvent. Use of Cinacalcet of formula I prepared by the claimed method in preparation of pharmaceutically acceptable salts of Cinacalcet.
- -
-
Page/Page column 9
(2013/06/06)
-
- A novel method for the large scale synthesis of cinacalcet hydrochloride using iron catalyzed C-C coupling
-
A novel synthetic route for commercial preparation of cinacalcet hydrochloride (1), a calcimimetic agent and calcium-sensing receptor antagonist, is described. Our synthetic approach involves the preparation of cinacalcet using C-C bond formation catalyzed by iron acetylacetonate/NMP complex with aryl Grignard reagent benzotrifluoride magnesium bromide (8) and alkenyl halide N-chloropropene naphthylethylamine (6).
- Tewari, Neera,Maheshwari, Nitin,Medhane, Roshan,Nizar, Hashim,Prasad, Mohan
-
p. 1566 - 1568
(2013/02/23)
-
- A novel asymmetric synthesis of cinacalcet hydrochloride
-
A novel route to asymmetric synthesis of cinacalcet hydrochloride by the application of (R)-tert-butanesulfinamide and regioselective N-alkylation of the naphthyl ethyl sulfinamide intermediate is described.
- Arava, Veera R.,Gorentla, Laxminarasimhulu,Dubey, Pramod K.
-
p. 1366 - 1373
(2012/10/29)
-
- PROCESS FOR CINACALCET HYDROCHLORIDE
-
3-[3-(Trifluoromethyl)phenyl]propionaldehyde is a key intermediate for the preparation of cinacalcet hydrochloride. The present invention provides a novel process for the preparation of 3-[3-(trifluoromethyl)phenyl]propionaldehyde. The present invention also provides an improved process for preparation of cinacalcet hydrochloride in high yields. The present invention further provides a process for purification of cinacalcet hydrochloride.
- -
-
-
- PROCESSES FOR THE PREPARATION OF CINACALCET
-
The present invention provides processes and intermediates for preparing cinacalcet base and pharmaceutically acceptable salts thereof.
- -
-
-
- PROCESS FOR PREPARING CINACALCET AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
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.
- -
-
-
- Method For The Preparation Of Cinacalcet And Intermediates And Impurities Thereof
-
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.
- -
-
-
- A process for the preparation of cinacalcet and intermediates thereof
-
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.
- -
-
-
- PROCESS FOR THE PREPARATION OF CINACALCET AND INTERMEDIATES THEREOF
-
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.
- -
-
-
- Industrial application of the forster reaction: Novel one-pot synthesis of cinacalcet hydrochloride, a calcimimetic agent
-
Described is a new, practical, and one-pot process, based on the Forster reaction, for the synthesis of cinacalcet hydrochloride (1), a calcimimetic agent and calcium-sensing receptor antagonist. The synthesis comprises the condensation of (1R)-(+)-1-naphthylethyl amine (2) with benzaldehyde (3) followed by reaction of obtained Schiff's base 4 with 1-(3-halopropyl)-3- (trifluoromethyl)benzene (5) to provide highly unstable iminium salt 6. Subsequent hydrolysis of 6 with water in the same pot yielded cinacalcet. The treatment of cinacalcet with hydrochloric acid during the workup process furnished 1 with an overall yield of around 60%. Our synthetic approach for 1, discussed in this report demonstrates industrial application of the century-old, unexplored name reaction, "Forster's Reaction" or Forster-Decker synthesis.
- Shinde, Gorakshanath B.,Niphade, Navnath C.,Deshmukh, Shrikant P.,Toche, Raghunath B.,Mathad, Vijayavitthal T.
-
experimental part
p. 455 - 461
(2012/05/19)
-
- PROCESS FOR PREPARING CINACALCET
-
A process for preparing N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)-phenyl]propan-1-amine of formula hydrochloride salt of formula (I); i.e. Cinacalcet.HC1 and its intermediate of formula (IX).
- -
-
Page/Page column 23-24
(2011/04/18)
-
- PROCESS FOR PREPARING CINACALCET HYDROCHLORIDE
-
A process for preparing N-[(1lR)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)- phenyl]propan-1-amine hydrochloride salt of formula (I) i.e. Cinacalcet hydrochloride and its intermediates of formulae (VII) and (VIII) wherein Z is chloride or another pharmaceutically acceptable anionic counterion.
- -
-
Page/Page column 28
(2010/09/17)
-
- PROCESS FOR THE PREPARATION OF CINACALCET AND SALTS THEREOF, AND INTERMEDIATES FOR USE IN THE PROCESS
-
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.
- -
-
Page/Page column 22
(2010/09/18)
-
- PROCESS FOR PREPARING CINACALCET AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
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.
- -
-
Page/Page column 44
(2010/04/03)
-
- UNSATURATED CINACALCET SALTS AND PROCESSES FOR PREPARING CINACALCET HYDROCHLORIDE
-
Disclosed herein are convenient, industrially advantageous and environmentally friendly processes for the preparation of cinacalcet hydrochloride. Disclosed also herein are novel hydrochloride, oxalate and di-p-toluoyl-L-(+)-tartrate salts of (R)-a-methyl-N-[3-[3- (trifluoromethyl)phenyl]propylene]-l -naphthalenemethaneamine (unsaturated cinacalcet), solid state forms of the salts, and a process for their preparation thereof.
- -
-
Page/Page column 22-23
(2010/04/03)
-
- HIGHLY PURE CINACALCET OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
-
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.
- -
-
Page/Page column 37-38
(2010/07/02)
-
- A NEW METHOD FOR THE PREPARATION OF CINACALCET AND NEW INTERMEDIATES THEREOF
-
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.
- -
-
Page/Page column 19-20
(2010/10/03)
-
- A PROCESS FOR THE PREPARATION OF CINACALCET AND ITS SALTS
-
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.
- -
-
Page/Page column 19
(2010/04/03)
-
- A process for the preparation of cinacalcet
-
The invention provides a novel process for the preparation of a compound of formula (I) comprising the reduction of a compound of formula (II) or a salt thereof, in the presence of a catalyst, and novel intermediates useful for its synthesis.
- -
-
Page/Page column 6
(2009/03/07)
-
- IMPROVED PROCESS FOR PREPARING CINACALCET HYDROCHLORIDE
-
The invention relates to an improved process for preparing cinacalcet hydrochloride. The invention provides an efficient and economic process for preparing cinacalcet hydrochloride which is suitable for industrial implementation i.e., affords cinacalcet hydrochloride with high purity, and uses small volumes of acidifying agent and solvents. The invention also related to a process for preparing a cinacalcet carboxylate salt, including cinacalcet acetate
- -
-
Page/Page column 6-9
(2009/04/25)
-
- A PROCESS FOR THE SYNTHESIS OF CINACALCET HYDROCHLORIDE
-
There is described a process for the preparation of cinacalcet hydrochloride (I) which includes the steps of: a) reacting (R)-(+)-1-(1-naphthyl)ethylamine (II) with 3-[3-(trifluoromethyl)phenyl]propenaldehyde (III) to afford the non isolated intermediate (R)-N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino-N-[1-(1 - naphthyi)ethy!amine (IV); b) reducing the non isolated intermediate (R)-N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimine-N-[-1 -(1 -naphthyl)ethylamine (IV) with a sequential addition of: - a solution of sodium borohydride, methanol and a base, - oxalic acid and - a base to obtain (R)-N-[3-[3-(trifluoromethyl)phenyl]-2- propenyl]-1-(1-naphthyl)ethylamine (V) by passing through the precipitation of the oxalate salt of compound (V) after the addition of oxalic acid; c) hydrogenating (R)-N-[3-[3-(trifluoromethyl)phenyl]-2-propenyl]-1 -(1 - naphthyl)ethylamine (V) thus obtaining (R)-N-(3-(3- (trifluoromethyl)phenyl]propyij-i-(i -naphthyl)ethylamine cinacalcet base (Vl), which is retaken in ethyl acetate; and d) treating the- solution of cinacalcet base (Vi) in ethyl acetate with hydrochloric acid to afford cinacalcet hydrochloride (I).
- -
-
Page/Page column 7-8
(2010/01/12)
-