364782-34-3

Usage

Originator

NPS pharmaceuticals (US)

Synthesis

General syntheses of this class of compounds have been published, however, the specific synthesis of cinacalcet (III) has not been available to date. The synthesis of cinacalcet, based on a patented procedure, is depicted in Scheme 3. A mixture of 1-acetonaphthone (21), 3-trifluoromethyl-1-propylamine (22) and titanium (IV) isopropoxide were stirred at rt to form the enamine intermediate which was reduced with methanolic sodium cyanoborohydride at rt to give corresponding racemic a-methyl amine (23). Compound 23 was resolved and then treated with HCl etherate to give cinacalcet hydrochloride (III) as a white solid.

references

[1] ure?a p1, fraz?o jm. calcimimetic agents: review and perspectives. kidney int suppl. 2003 jun;(85):s91-6.[2] colloton m1, shatzen e, wiemann b, starnes c, scully s, henley c, martin d.cinacalcet attenuates hypercalcemia observed in mice bearing either rice h-500 leydig cell or c26-dct colon tumors. eur j pharmacol. 2013 jul 15;712(1-3):8-15.

InChI:InChI=1/C22H22F3N.ClH/c1-16(20-13-5-10-18-9-2-3-12-21(18)20)26-14-6-8-17-7-4-11-19(15-17)22(23,24)25;/h2-5,7,9-13,15-16,26H,6,8,14H2,1H3;1H/t16-;/m1./s1

Synthetic route

(R)-N-(1-(naphthalen-1-yl)ethyl)-N-(3-(3-(trifluoromethyl)phenyl)propyl)formamide (1601479-86-0) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogenchloride In water for 12h; Reflux;	100%

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + methylsulfonyl-3-(3-trifluoromethylphenyl)propyl ester (21172-43-0) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-1-(1-Naphthyl)ethylamine; methylsulfonyl-3-(3-trifluoromethylphenyl)propyl ester With potassium carbonate; potassium iodide; 1-(n-butyl)-3-methylimidazolium triflate In acetonitrile for 6h; Reflux; Stage #2: With hydrogenchloride at 50 - 55℃; for 1h; Reagent/catalyst;	98.25%
Stage #1: (R)-1-(1-Naphthyl)ethylamine; methylsulfonyl-3-(3-trifluoromethylphenyl)propyl ester With potassium carbonate In toluene for 16h; Reflux; Stage #2: With hydrogenchloride In water; toluene at 70℃; Reagent/catalyst; Solvent; Temperature; Time;	85%

(R)‐N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide (1005450-55-4) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)‐N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide With sodium tetrahydroborate; iodine In tetrahydrofuran at 0 - 75℃; for 6.5h; Stage #2: With hydrogenchloride In hexane; water for 1h;	96.22%
Stage #1: (R)‐N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide With sodium tetrahydroborate; boron trifluoride In tetrahydrofuran; diethylene glycol dimethyl ether at 45 - 60℃; Stage #2: With hydrogenchloride In toluene Further stages.;	95%
Stage #1: (R)‐N‐(1‐(naphthalen‐1‐yl)ethyl)‐3‐(3‐trifluoromethylphenyl)propanamide With dodecacarbonyl-triangulo-triruthenium; 1,1,3,3-tetramethyldisilazane In toluene at 50℃; for 18h; Stage #2: With hydrogenchloride In 1,4-dioxane at 50℃;	93%

cinacalcet (226256-56-0) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogenchloride In n-heptane; ethyl acetate at 20℃;	95%
With hydrogenchloride In acetonitrile at 25 - 55℃; for 0.2h;	93.1%
With hydrogenchloride In n-heptane; water; toluene at 25 - 30℃; pH=1 - 2; Product distribution / selectivity;	92.55%

(R)-α-methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalenemethanamine phosphate → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-α-methyl-N-[3-[3-trifluoromethylphenyl]propyl]-1-naphthalenemethanamine phosphate With sodium hydroxide In water; ethyl acetate at 20℃; for 1h; Inert atmosphere; Stage #2: With hydrogenchloride In ethyl acetate at 20 - 25℃;	94%

vinyl acetate (108-05-4) + 1-(1-naphthyl)ethanol (57605-95-5) + 3‐[3‐(trifluoromethyl)phenyl]propan‐1‐amine (104774-87-0) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: vinyl acetate; 1-(1-naphthyl)ethanol at 30℃; for 12h; Enzymatic reaction; Stage #2: 3‐[3‐(trifluoromethyl)phenyl]propan‐1‐amine With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 25℃; Stage #3: With hydrogenchloride In water Solvent;	93.3%

cinacalcet L-tartrate → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: cinacalcet L-tartrate With sodium carbonate In water at 15 - 20℃; Inert atmosphere; Stage #2: With hydrogenchloride In water; acetonitrile at 15 - 20℃; for 0.5h;	92.54%

N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine hydrochloride (1240705-66-1) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogen; palladium dichloride In methanol; ethyl acetate at 20℃; under 750.075 Torr; for 0.5h; Product distribution / selectivity;	92.5%

(R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl-2-ene]-1-naphthalenemethaneamine hydrochloride (1207533-91-2) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With palladium on activated charcoal; hydrogen In water; ethyl acetate at 25 - 30℃; Large scale;	91%
With palladium 10% on activated carbon; hydrogen; potassium carbonate In methanol at 20 - 25℃; under 1500.15 - 2250.23 Torr; for 3h; pH=4.1;	71%
With hydrogen; Raney nickel In methanol; ethyl acetate at 20℃; Product distribution / selectivity; Inert atmosphere;	69.6%
With hydrogen; palladium(II) hydroxide In methanol at 5 - 10℃; under 1103.36 Torr; for 3h; Product distribution / selectivity; Autoclave;
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / ethyl acetate; water / 1 h / 20 °C / Inert atmosphere 1.2: 1 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride; hydrogen / 2-5percent w/w palladium on carbon / water; methanol / 20 - 30 °C / Inert atmosphere View Scheme

2-methylpropane-2-sulfinic acid (1-naphthalen-1-ylethyl)-[3-(3-trifluoromethylphenyl)propyl]amide (1410044-63-1) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogenchloride In tert-butyl methyl ether; water at 20℃;	91%

Sodium 1-hydroxy-3-(3-trifluoromethylphenyl)propane-1-sulfonate (1015421-30-3) + (R)-<1-(1-Naphthyl)ethyl>ammonium chloride (82572-04-1) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: Sodium 1-hydroxy-3-(3-trifluoromethylphenyl)propane-1-sulfonate; (R)-<1-(1-Naphthyl)ethyl>ammonium chloride With triethylamine-borane In methanol at 20℃; for 16h; Stage #2: With hydrogenchloride In water at 0℃; for 13h; Reagent/catalyst;	91%

(R)-(1-(naphthalen-1-yl)-ethyl)-[3-(3-trifluoromethyl-phenyl)-prop-2-ynyl]-amine hydrochloride (1093944-40-1) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogen; 5%-palladium/activated carbon In water; isopropyl alcohol at 20℃; for 3h;	90%
With hydrogen; 5%-palladium/activated carbon In isopropyl alcohol at 20℃; under 760.051 Torr; for 3h;	90%

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + 3-(3-(trifluoromethyl)phenyl)propyl trifluoromethanesulfonate → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-1-(1-Naphthyl)ethylamine; 3-(3-(trifluoromethyl)phenyl)propyl trifluoromethanesulfonate With potassium hydroxide In toluene for 16h; Reflux; Stage #2: With hydrogenchloride In water; toluene Temperature;	89%

N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-tritylamine → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogenchloride In tert-butyl methyl ether; water at 20℃;	84%

N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine fumarate → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogenchloride; hydrogen; 2-5percent w/w palladium on carbon In methanol; water at 20 - 30℃; Inert atmosphere;	83.8%

1-(3-bromopropyl)-3- (trifluoromethyl)benzene (129254-76-8) + (R)-1-(1-Naphthyl)ethylamine (3886-70-2) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: 1-(3-bromopropyl)-3- (trifluoromethyl)benzene; (R)-1-(1-Naphthyl)ethylamine With potassium carbonate In toluene for 7h; Reflux; Stage #2: With hydrogenchloride In water; toluene at 50℃;	83%
Stage #1: (R)-1-(1-Naphthyl)ethylamine With benzaldehyde at 25 - 30℃; Forster reaction; Stage #2: 1-(3-bromopropyl)-3- (trifluoromethyl)benzene In 1-methyl-pyrrolidin-2-one at 125 - 130℃; Forster reaction; Further stages;	58%

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + 3-[3-(trifluoromethyl)phenyl]propan-1-ol (78573-45-2) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-1-(1-Naphthyl)ethylamine; 3-[3-(trifluoromethyl)phenyl]propan-1-ol With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)] In toluene at 110℃; for 6h; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; hexane; ethyl acetate; toluene Reagent/catalyst; Time;	83%

(R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (1273259-52-1) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride With sodium hydrogencarbonate In water; toluene at 15 - 20℃; pH=8 - 9; Inert atmosphere; Stage #2: With hydrogen; 5% Pd(II)/C(eggshell) In methanol; toluene at 20℃; under 750.075 Torr; Product distribution / selectivity;	82.6%

N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]propan-1-amine bisulfate → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 20℃;	80.8%

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + 3-[3-(trifluoromethyl)phenyl]propanal (21172-41-8) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-1-(1-Naphthyl)ethylamine; 3-[3-(trifluoromethyl)phenyl]propanal With sodium tetrahydroborate; boric acid at 20℃; for 14.5h; Stage #2: With hydrogenchloride In hexane; water at 20℃; for 3.5h; pH=1 - 3;	80%
Stage #1: (R)-1-(1-Naphthyl)ethylamine; 3-[3-(trifluoromethyl)phenyl]propanal In tetrahydrofuran at -50 - -45℃; for 2.5h; Stage #2: With titanium(IV) isopropylate In tetrahydrofuran Product distribution / selectivity;

N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane acetate (1025064-29-2) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With sodium chloride In 2-methylpropyl acetate; water at 20℃; Product distribution / selectivity;	79.7%
With hydrogenchloride In 2-methylpropyl acetate; water at 5 - 10℃; for 0.5h; Product distribution / selectivity;	72.7%
With hydrogenchloride In dichloromethane; water for 0.25h; Product distribution / selectivity;

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + 3-(3-trifluoromethylphenyl)propanoic acid (585-50-2) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-1-(1-Naphthyl)ethylamine; 3-(3-trifluoromethylphenyl)propanoic acid With platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex; phenylsilane; 1,2-bis-(diphenylphosphino)ethane In dibutyl ether at 120℃; for 18h; Schlenk technique; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether at -20℃; Schlenk technique; Inert atmosphere;	74%

(R)-1-(1-Naphthyl)ethylamine (3886-70-2) + 1-(3-chloropropyl)-3-(trifluoromethyl)benzene (82258-76-2) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-1-(1-Naphthyl)ethylamine; 1-(3-chloropropyl)-3-(trifluoromethyl)benzene With potassium carbonate In toluene for 15h; Reflux; Stage #2: With hydrogenchloride In water; toluene for 60h;	73%

methylsulfonyl-3-(3-trifluoromethylphenyl)propyl ester (21172-43-0) + (R)-<1-(1-Naphthyl)ethyl>ammonium chloride (82572-04-1) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In water; toluene for 24h; Inert atmosphere; Reflux;	71.8%

N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine citrate → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine citrate With hydrogen; 2.5% wt Pd/C In methanol Inert atmosphere; Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃; for 1h; Product distribution / selectivity; Inert atmosphere;	63.9%

(R)-N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino]-N-[1-(1-naphthyl)ethylamine] (1201910-95-3) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino]-N-[1-(1-naphthyl)ethylamine] With 5%-palladium/activated carbon; hydrogen In ethanol at 20℃; under 2250.23 Torr; Stage #2: With hydrogenchloride In ethanol; isopropyl alcohol	60%

1'-naphthacetophenone (941-98-0) + 3‐[3‐(trifluoromethyl)phenyl]propan‐1‐amine (104774-87-0) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: 1'-naphthacetophenone; 3‐[3‐(trifluoromethyl)phenyl]propan‐1‐amine With (R)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diylhydrogenphosphate In toluene at 40℃; for 48h; Molecular sieve; Inert atmosphere; Stage #2: With hydrogenchloride In water; toluene at 0 - 5℃; Reagent/catalyst;	56.7%

1-(3-bromopropyl)-3- (trifluoromethyl)benzene (129254-76-8) + (R)-1-(1-Naphthyl)ethylamine (3886-70-2) + benzaldehyde (100-52-7) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-1-(1-Naphthyl)ethylamine; benzaldehyde at 25 - 30℃; Stage #2: 1-(3-bromopropyl)-3- (trifluoromethyl)benzene In 1-methyl-pyrrolidin-2-one at 130 - 140℃; for 12h; Stage #3: With hydrogenchloride; water In 1-methyl-pyrrolidin-2-one; toluene pH=0.5 - 2;	52.1%

(E)-N-((R)-1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-acrylamide (1095393-66-0) → cinacalcet hydrochloride (364782-34-3)

Conditions	Yield
Stage #1: (R)-N-(1-naphthalen-1-yl-ethyl)-3-(3-trifluoromethyl-phenyl)-(E)-acrylamide With dimethylsulfide borane complex In tetrahydrofuran at 0 - 65℃; for 4h; Stage #2: With methanol at 0℃; for 0.5h; Stage #3: With hydrogenchloride; water at 0 - 90℃; for 4h; Product distribution / selectivity;

cinacalcet hydrochloride (364782-34-3) → cinacalcet (226256-56-0)

Conditions	Yield
With sodium carbonate In dichloromethane; water	96%
With water; sodium carbonate In di-isopropyl ether at 25℃; for 2.25h; pH=9.5;

cinacalcet hydrochloride (364782-34-3) + benzyl bromide (100-39-0) → C29H28F3N

Conditions	Yield
With potassium carbonate In acetonitrile at 100℃; for 12h; Inert atmosphere;	82%

cinacalcet hydrochloride (364782-34-3) + 1-(3-bromopropyl)-3- (trifluoromethyl)benzene (129254-76-8) → (R)-(1-naphthalen-1-ylethyl)-N,N-bis[3-(3-trifluoromethylphenyl)propyl]amine (1271930-15-4)

Conditions	Yield
With potassium carbonate In toluene at 110 - 111℃; for 48h;	69.03%

Upstream product

• 226256-56-0 cinacalcet 
• 1093944-40-1 (R)-(1-(naphthalen-1-yl)-ethyl)-[3-(3-trifluoromethyl-phenyl)-prop-2-ynyl]-amine hydrochloride 
• 1204313-91-6 (R)-tert-butyl (1-(naphthalen-1-yl)ethyl)(3-(3-(trifluoromethyl)phenyl)propyl)carbamate 
• 1204313-93-8 (R)-4-nitro-N-(1-naphthalen-1-yl-ethyl)-N-[3-(3-trifluoromethyl-phenyl)-propyl]-benzene sulphonamide 
• 1207533-91-2 (R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl-2-ene]-1-naphthalenemethaneamine hydrochloride 
• 1073144-62-3 (1R)-1-(naphthalen-1-yl)ethanamine (R)-mandelate 
• 21172-43-0 methylsulfonyl-3-(3-trifluoromethylphenyl)propyl ester 
• 1240705-66-1 N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine hydrochloride 
• 65126-85-4 3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-ol 
• 78573-45-2 3-[3-(trifluoromethyl)phenyl]propan-1-ol 
• 21172-41-8 3-[3-(trifluoromethyl)phenyl]propanal 
• 518335-32-5 tert-butyl (R)-1-(naphthalen-1-yl)ethylcarbamate 
• 585-50-2 3-(3-trifluoromethylphenyl)propanoic acid 
• 1204313-92-7 (R)-N-(1-naphthalen-1-yl-ethyl)-4-nitro-benzenesulfonamide 

Downstream Products

• 226256-56-0 cinacalcet 
• 1271930-15-4 (R)-(1-naphthalen-1-ylethyl)-N,N-bis[3-(3-trifluoromethylphenyl)propyl]amine 
• 1301700-82-2 1-chloroethyl carbamate cinacalcet 

Relevant academic research and scientific papers

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.

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.

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.

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.

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.

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.

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.

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.